Genetic Perils: Allopurinol Hypersensitivity Syndrome and Personalized Medicine

Allopurinol hypersensitivity syndrome (AHS) affects approximately 1 in 1,000 patients prescribed allopurinol, with reported mortality rates between 20% and 25%. The risk of AHS is nearly 100 times higher in carriers of the HLA-B*58:01 allele than in noncarriers. Populations with a high allele frequency include Han Chinese (6%-8%), Korean (12%), and Thai (6%-8%) people.

In this episode, Drs. Wid Yaseen and Jonathan Zipursky discuss their paper published in CMAJ, titled "Five things to know about…allopurinol hypersensitivity syndrome". Dr. Jonathan Zipursky is a general internist, clinical pharmacologist, and clinician scientist at Sunnybrook Health Sciences Centre. Dr. Yaseen is a second-year internal medicine resident physician at the University of Toronto. They argue that the syndrome's frequency is often underestimated and emphasize the importance of genetic testing in susceptible populations.

Next, Dr. David Juurlink broadens the discussion beyond allopurinol to describe other common medications whose effectiveness and safety are significantly influenced by genetic predispositions. Dr. Juurlnk is a staff internist and head of division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto. He is also a medical toxicologist at the Ontario Poison Centre.  He explores the need for expanded genetic testing to protect patients and ensure proper dosing.

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Transcript

Dr. Mojola Omole:

Hi, I'm Mojola Omole.

Dr. Blair Bigham:

I'm Blair Bigham. This is a CMAJ podcast.

Dr. Mojola Omole:

So today, Blair, we're going to be talking about the five things you need to know about allopurinol hypersensitivity. So for me, allopurinol is one of those medications that I see a lot of patients with. And so reading about the hypersensitive syndrome was really interesting.

Dr. Blair Bigham:

And there's so many drugs that sort of flag in my mind as drugs to watch out for, drugs to provide caution with. But allopurinol isn't necessarily one of those that are top of mind when I put somebody on it, prescribe it, or when I see somebody come into the ER and they're already on it. So I think this is sort of a really interesting one to highlight today.

So today we're going to talk to the authors about this hypersensitivity syndrome and then we're going to talk to David Juurlink, a clinical pharmacologist and toxicologist who's going to expand the conversation beyond allopurinol, to talk about other drugs that we should all be maybe a little bit more cautious of prescribing.

Dr. Wid Yaseen and Dr. Jonathan Zipursky are co-authors of the practice paper in CMAJ entitled "Five things to know about…: Allopurinol hypersensitivity syndrome". Dr. Jonathan Zipursky is a general internist, clinical pharmacologist and clinician scientist at Sunnybrook Health Sciences Centre, and Dr. Yaseen is a second year internal medicine resident physician at the University of Toronto. Thank you so much for joining us.

Dr. Wid Yaseen:

Thanks for having us.

Dr. Jonathan Zipursky:

Thanks. It's great to be here.

Dr. Blair Bigham:

Tell us, what were you seeing in your clinical practice that sparked you to write this paper on allopurinol hypersensitivity syndrome?

Dr. Jonathan Zipursky:

That's a great question, Blair. So the rationale for writing the paper was mainly twofold. Firstly, as a clinical pharmacologist, I tend to see a lot of hypersensitivity drug reactions and allopurinol is one of those culprit drugs that is known to cause hypersensitivity reactions. And our goal was to highlight this as a potential serious adverse drug reaction that we felt that the general population should know about.

And the second piece was that there are some genetic factors that might put certain people at risk of developing this hypersensitivity reaction. And we felt that those genetic tests and those genetic susceptibilities were underappreciated and we wanted to highlight that for other physicians. Mainly, that allopurinol is such a commonly used drug and we felt that people weren't ordering the HLA testing as frequently as maybe they should be. And so that was really one of the major things we wanted to highlight for other colleagues and other healthcare providers that perhaps we should be ordering this test more frequently.

Dr. Blair Bigham:

So before we get into the genetics of the syndrome, I'd never even heard of it before. It had never come up in residency as far as I can remember. What's the prevalence of it? Is it common?

Dr. Wid Yaseen:

It's pretty rare. It's 1 in 1000 people who are prescribed allopurinol can develop allopurinol hypersensitivity syndrome, but the mortality is pretty high, up to 25% of people can die with this condition.

Dr. Blair Bigham:

So tell us more about the actual syndrome. It's sort of like a Stevens-Johnson's reaction.

Dr. Wid Yaseen:

It's a severe cutaneous adverse reaction, so encompasses a few clinical syndromes including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms. And patients usually present with a rash, they can present with fever, evidence of multi-organ involvement like kidney impairment and liver injury, and evidence of peripheral eosinophilia on their blood work. And usually they can present actually a few weeks after being started on this medication.

Dr. Blair Bigham:

A few weeks.

Dr. Wid Yaseen:

Mm-hmm.

Dr. Blair Bigham:

Oh, okay.

Dr. Mojola Omole:

How does it differ across populations?

Dr. Wid Yaseen:

In terms of susceptibility or...?

Dr. Mojola Omole:

In terms of prevalence.

Dr. Wid Yaseen:

So there's been haplotypes that have been associated with increased risk of developing allopurinol hypersensitivity syndrome, including the HLA B5801 allele, which Jon alluded to earlier. In patients who are carriers of this allele, they are  at a much increased risk of developing this adverse drug reaction and the allele frequency is highest in certain populations including those of East Asian descent like Han Chinese, Thai and Korean populations.

Dr. Blair Bigham:

So tell us more about the way we should be testing for this gene before prescribing allopurinol because it never had crossed my mind before.

Dr. Wid Yaseen:

So the first step is really identifying patients who might be at increased risk, and one of the populations that are at increased risks are those who are carriers of theHLA-B*58:01 allele. And those include certain ethnic populations including those of East Asian descent. Other risk factors include patients who have chronic kidney disease and patients who have cardiovascular risk factors. And so in patients who are being prescribed allopurinol who have these risk factors, it's important to think about mitigating the risk. And for patients who may be carriers of the haplotype, that's when genetic testing can be indicated.

Dr. Mojola Omole:

So what's the pathophysiology of having the sensitivity?

Dr. Jonathan Zipursky:

So I think the major risk factors that had been identified previously, the card... it's more chronic in disease and cardiovascular risk factors. There was a large study actually published in CMAJ a few years ago, big observational study that identified those as the two main risk factors associated with developing adverse drug reactions to allopurinol or allopurinol hypersensitivity syndrome.

The pathophysiology behind the chronic kidney disease is thought to be perhaps related to drug clearance. The drug is metabolized and then eventually renally cleared. And that's why in those who have poor renal clearance, perhaps, the drug metabolites are achieving higher concentrations. So that's why the guidelines suggest starting low dose allopurinol in most patients, but especially in those who have evidence of chronic renal disease to start at an even lower dose and then titrate up to treatment effect, but also being mindful of the potential adverse reactions. And so the HLA testing is, it is available pretty readily in Canada and the guidelines suggest identifying patients that might be at slightly higher risk based on race or ethnicity and then sort of risk stratifying that way. Allopurinol is  so ubiquitously used it would be very difficult to encourage testing for absolutely everybody for HLA-B*58:01.

Dr. Blair Bigham:

I want to ask more about the HLA testing because I can imagine for a lot of physicians they might be hesitant. I mean, I guess you'd have to memorize HLA-B*58:011. A lot of people might not be testing that all the time. In the ER, I'm never going to order that test. Is it expensive? How long does it take? Does it have to get flown somewhere to be done or is it something that any lab would do?

Dr. Jonathan Zipursky:

So not all labs will do HLA-testing, I think that's an important point. In most provinces we can access that test. For example, in Toronto, when I'm sending the lab test off, we don't run that test on our center, we actually send it down to the University Health Network to run that test. But most, if you look, most hospitals or health systems will have a cadre of pharmacogenetic testing you can order. And of course it's very difficult to remember which specific pharmacogenetic refers to which syndrome. But oftentimes they have selections of like HLA-B*58:01 is associated with allopurinol hypersensitivity syndrome so that physicians can... So cues physicians into like, "This is the correct one to be ordering."

Dr. Mojola Omole:

Is it OHIP covered?

Dr. Jonathan Zipursky:

It is OHIP covered. I believe if you're doing it through the hospital, it's OHIP covered. I would imagine if you're doing it in an outside lab, there is a cost associated with it, but off the top of my head I don't have the cost of it.

Dr. Mojola Omole:

I guess my question then becomes should family physicians be... like if we're saying that they should test for this, how can they access that if it's only OHIP covered through the hospital network?

Dr. Jonathan Zipursky:

Yeah, that's a great question. I think it is important, especially again, we're not advocating for testing in all patient populations. I think there's some differing in guidelines about that right now. But in terms of the guidelines that we're using, I think we should be testing in high risk populations that we'd sort of highlighted before. How to get access to it, I think, you're right, this may be a bit of an equity issue that if they're not getting it done in the major hospital systems and if it's not OHIP covered, it may limit access.

I mean, as a sort of a spinoff of why we wrote this piece, perhaps this is a reason to be advocating for coverage for some of these tests. We really think it's an important... Pharmacogenetics, there are lots of pharmacogenetic associations, but this is one that we feel is actually a really important one. And so as part of why we wrote this piece perhaps, this is a reason to consider advocating for some of these pharmacogenetic tests to be covered.

Dr. Blair Bigham:

We were looking at the frequency of this particular allele and there's a couple of populations that sort of score off the chart. Thai populations, Han Chinese populations, South Korean populations, and then right in the middle of the chart were African Americans. Should Black patients also be screened or is the payoff not quite there with the pre-test probability?

Dr. Wid Yaseen:

Yeah, it's a really good question and it's an area of interest right now. Like the most recent American guidelines do recommend screening African-American patients for the haplotype. But in terms of the risks associated with developing the drug reaction, actually some studies have shown that despite the increased allele frequency within the African American population, the risk of developing the adverse drug reaction was not appreciated. And so it poses a question about the genetic variability within the black population, that's a high genetic variability within the population that doesn't necessarily translate to an increased risk of the adverse drug reaction.

So I think it is a really good question and maybe in the future we'll see more research that includes Black patients, especially in Canada, because most of the research from Canada comes out of the East Asian population, particularly in British Columbia, which supports screening those populations here.

Dr. Blair Bigham:

I want to get into some practical prescribing tips, but first I want to ask how do you pick up this drug reaction if it's happening? When do people present? And how quickly does it become full-blown where you're suddenly at a pretty high mortality risk?

Dr. Wid Yaseen:

So after being prescribed allopurinol, some patients and the counseling is usually to... We should be counseling patients to look out for symptoms like developing a new rash or new fevers or feeling unwell. And typically patients may present with this about eight or nine weeks after being started on allopurinol.

Dr. Blair Bigham:

So it's pretty somewhat delayed in a sense.

Dr. Jonathan Zipursky:

Yeah, that's the classic course. Oftentimes we think of drug reactions as somebody taking a drug and developing a reaction immediately. This is one of these examples where when we see it clinically, the classic patient course is somebody who's been on it for weeks if not months, and then they develop symptoms. And oftentimes one of the reasons why this can be so hard to pick up is it often starts with a viral prodrome. It almost looks like you've had the flu and it's treated as having a viral infection. And then a couple days later, that's when we start to see the rash. That's when we start to see some of the other blood work abnormalities. So that's somewhat of an insidious type of reaction. It can be very difficult to pick up sometimes. So that's why we would sort of advocate for if somebody's been on this medication for that critical time period, which is several weeks to months and they start having flu-like symptoms, fevers, any sign of a rash, that they seek medical attention., and they stop the drug immediately.

Dr. Blair Bigham:

So someone comes in, we know that you diagnose them clinically with the hypersensitivity, what's the treatment pathway?

Dr. Jonathan Zipursky:

So the treatment pathway varies to some extent on the severity and also on the subtype of the syndrome that they have. First and foremost, it's stopping the drug. That's critical. And secondly, good supportive care. I think patients with SJS or TN oftentimes need to be in a very high level of care. Where I work at Sunnybrook, we have a burn unit, so those patients are treated in our burn unit. Oftentimes, in places where there isn't a burn unit, they're treated in an intensive care unit.

But again, there is a spectrum and sometimes if it's not particularly severe, stopping the drug may be just good enough. If there's evidence of internal organ involvement, oftentimes we start steroids, which is often a prolonged course of steroids. And then there are some adjunct treatments depending on if it is SJS or TEN, sometimes we use drugs like cyclosporine or some of the TNF-alpha inhibitors. But again, it depends on whether it's distress type syndrome, how severe it is, or if it is the SJS, TEN phenotype. The nuance treatment actually differs a little bit. The consistent treatment is stopping the drug with excellent supportive care.

Dr. Blair Bigham:

So allopurinol, super-common prescription. Can you give us some really practical tips to reduce the risk of allopurinol hypersensitivity syndrome? You had mentioned starting at a low dose. What doses are we talking about and how do you gradually titrate up to have a treatment effect?

Dr. Wid Yaseen:

The recommendation is that if patients have... So number one, in patients who are positive for the genetic test, they should not be started on allopurinol. If they have other risk factors like, for example, chronic kidney disease, the recommendation is to start low at less than 50 milligrams a day and based on the patient's tolerance, then you can increase the dose.

Dr. Blair Bigham:

Okay. And then in terms of alternatives, what else could people consider instead of using allopurinol?

Dr. Wid Yaseen:

So febuxostat is the other urate lowering drug, and it's just as effective as allopurinol, but it is considered second line because it's associated with some cardiovascular risks and drug-induced liver injury. So typically, the medication is usually only covered in patients who can't tolerate allopurinol.

Dr. Blair Bigham:

Okay. Or in those populations who are HLA positive, that would be a hard stop to go to that second line therapy right off?

Dr. Wid Yaseen:

Exactly.

Dr. Jonathan Zipursky:

Exactly. Yeah.

Dr. Wid Yaseen:

Exactly.

Dr. Blair Bigham:

Any other tips that you would have for family doctors or emergency doctors and other people who are prescribing allopurinol?

Dr. Jonathan Zipursky:

I think Wid has touched on the major ones, start low and slow, particularly those who have risk factors. I think in those that are in high risk populations, we certainly suggest testing for, assuming it's available and accessible, testing for theHLA-B*58:01. And I think a really important thing for most providers to know is that is if somebody's on the allopurinol and there's any signs of a flu-like illness or there's any developing rash, especially in that critical time period, which is weeks to months after the new start of the drug, that should be... the treatment should be stopping allopurinol first and foremost and reassessing.

Dr. Blair Bigham:

Perfect. Thank you so much for joining us today.

Dr. Jonathan Zipursky:

Thanks. It was fun.

Dr. Wid Yaseen:

Thanks for having us.

Dr. Blair Bigham:

Dr. Jonathan Zipursky is a general internist, clinical pharmacologist and clinician scientist at Sunnybrook Health Sciences Centre. And Dr. Wid Yaseen is a second year internal medicine resident physician at the University of Toronto.

Dr. Mojola Omole:

So we're now going to expand the conversation around adverse drug reactions beyond allopurinol, and we're very lucky that Dr. David Juurlink is here to help us. He's a staff internist and a head of division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto. He's also a medical toxicologist at the Ontario Poison Center at the Hospital for Sick Kids. And he's also a Twitter celebrity in the med Twitter world. Thank you so much for joining us today, David.

Dr. David Juurlink:

Thanks for having me.

Dr. Mojola Omole:

So we just heard about the risk of allopurinol for specific populations. So both me and Blair, were we asleep during that part of medical school or residency? Because I don't remember that being highlighted at all.

Dr. David Juurlink:

I certainly learned nothing about this, but I went through, I'm guessing, I went through school or before you guys did. I finished in '94, but I still don't think it's taught all that well or all that much. I do think that trainees who come through today have a greater awareness about drug reactions than we did maybe 20 or 30 years ago. But this aspect of genetics is still in its infancy in a way, and I think it's something that people will be expected to know more about as time goes on.

Dr. Mojola Omole:

So what are some other common prescribed medications that come with an increased risk for certain populations?

Dr. David Juurlink:

I think the best studied drug is probably abacavir, which is a drug for HIV and it's got a different HLA association B 5701. That's about somewhere between 5 and 8% of Europeans have this. The Han Chinese between 1 and 5%. But in Japanese people it's extremely rare, but I think it's standard of care now. Docs who look after patients with HIV, I don't think they'll start abacavir without testing for this HLA because of the association so strong.

Other common drugs that come to mind, there are some we use mainly in hospitals like vancomycin, but carbamazepine, a drug that we use for seizure disorders or for neuropathies and sometimes for mental health problems, that's got a strong association with an HLA called B 1502. And here again Han Chinese around 1.5 to 7%, and vanishingly rare in Japanese. And dapsone, a drug that we sometimes used for immunological disorders and certain skin conditions, again, about 1 in 20 Han Chinese will test positive for 1301. These are all different HLAs that impart an increased risk of severe and potentially life-threatening drug reactions that I think they're worth knowing about.

Dr. Blair Bigham:

David, we've been focusing on drugs that can kill you. What about the drugs that just don't work occasionally in some of these populations?

Dr. David Juurlink:

This is a really good question. And so two classic examples here that most docs will be familiar with would be codeine and clopidogrel. So codeine, which you can buy without a prescription in Canada, but most of us have prescribed it or even taken it. It doesn't do anything. Codeine has to be converted by the liver into morphine, its main active metabolite. And the enzyme in the liver that does that, it goes by the complicated name, cytochrome P450 2D6, or CYP2D6, for short.

Dr. Blair Bigham:

Oh yes, of course.

Dr. David Juurlink:

Yeah. Makes a small little change to the coding molecule and turns it into morphine. So that enzyme is very polymorphic, meaning that some of us don't have any of it. If you are of European descent, it depends what country you're from, but about 6% of Canadians who are of European descent don't have any of this enzyme and will convert exactly no codeine into morphine. So you can give them 60 of codeine, 120 of morphine, it won't do anything. So sometimes you'll hear people say, "Codeine doesn't work for me," and the reason it doesn't work for them may well be because they cannot turn it into morphine.

In contrast with codeine, there are some other populations that have extra copies of the gene that turns it into morphine. And so, especially in the Middle East, so about a third of people in, if you go to eastern Africa, so Ethiopia for example, or Somalia, or in the Arabian Peninsula, about 20 to 30% of people will have extra copies of the gene and they will turn codeine into morphine more efficiently.

So in other words, when you give somebody a known dose of codeine, what you're really doing is giving them an unknown dose of morphine. And this gets at Blair's question about drugs not working, or genetic influences that might undermine the therapeutic response. Another great example is clopidogrel, a drug that we use quite a lot in patients who had cardiovascular disease and stroke.

So clopidogrel is another drug that on its own doesn't do anything. It has to be turned into its active metabolite, like codeine. It's a different enzyme that does that,  it's called CYP2C19. This is an interesting one because there are some people who cannot turn clopidogrel on, they just lack altogether, the enzymes that do that. So Black populations about 2 to 5%. Asian populations up to a quarter of them cannot turn clopidogrel into its active metabolite. And on the other end of the spectrum, there are people who've got extra copies of the gene that do this, so they'll activate clopidogrel just fine. About 40% of Caucasians are ultra rapid metabolizers, meaning that they will convert clopidogrel very effectively into its active metabolite.

So there's a long list of enzymes that turn drugs on and turn drugs off. But to your question, Blair, about the genetic determinants of that, that's also widely available. We can easily test with a buccal swab or sometimes with blood testing. And patients, I'm sure, most doctors listening to this will have had a patient bring to them the results of pharmacogenetic testing that says, "I'm an ultra rapid 2C19, and what on earth does that mean?" And we could infer right now that it would mean that you would probably have a good response to clopidogrel.

Dr. Blair Bigham:

I feel like in real life most people aren't getting that genetic testing or doctors aren't ordering it. And so I'm curious, how does... Do things right now, you know, you get put on clopidogrel and what? It's not working. Nobody knows until you have another MI or you block stent.

Dr. Mojola Omole:

That's what I was thinking.

Dr. David Juurlink:

Yeah, so it's easy with codeine because you can tell whether the patient's had a response or not, right? It's more problematic with clopidogrel, and I think most places now are testing, or should be testing, because if you've had a couple of stents placed and you're on aspirin and clopidogrel and you cannot turn clopidogrel into its active metabolite, you're effectively not on clopidogrel. So I think a lot of hospitals are checking CYP2C19 status and if the patient happens to be a poor or intermediate metabolizer, they just use something else, like ticagrelor, in the case of cardiac disease.

Dr. Blair Bigham:

And this is happening in real life right now? People are ordering these genetic tests?

Dr. David Juurlink:

It happens, I think, to varying degrees by site. Where I see the testing happen... Occasionally, I'll see a patient who brings to me a report that they got done at, typically a concierge medicine clinic, that they've paid a few hundred dollars for and it spits out their entire, I won't say entire metabolic profile, but it'll tell you what their makeup is for a dozen or so cytochrome P450s. And it is kind of useful sometimes.

So another really important example, because so many people are on these drugs, is PPIs. So PPIs, here are drugs that are active that aren't turned into an active metabolite. When you give somebody omeprazole or pantoprazole, it's active and ready to go. Those drugs are metabolized by the same enzyme, CYP2C19, that happens to turn clopidogrel on.

If you have somebody who has helicobacter pylori and you put them on a PPI based regimen to try and eradicate it, what we know is that one reason why that regimen might fail is because people just have the genetic machinery that lets them chew through the PPI much more quickly. And so one way of getting around that is just to intensify the dose. And so this is increasingly being adopted as part of the management-

Dr. Mojola Omole:

You say that, but I'm someone who's on a PPI and I still have symptoms, but I also do eat bad foods. And so I'm like, "Wait, do I not maybe metabolize this?" And also as someone who scopes patients and puts people on PPIs, I have patients who've been on... I've done two different regimens for H. pylori eradication and we can't eradicate it. Now I'm like, "Wait."

Dr. David Juurlink:

So are your patients also Black?

Dr. Mojola Omole:

Some are.

Dr. David Juurlink:

Because 45% of people who are Black are ultra rapid metabolizers in CYP2C19. So what that means is they will have a great response to clopidogrel, but they might not respond to a PPI because they just break it down too quickly. So that's-

Dr. Mojola Omole:

Well I feel like a terrible doctor because I'm just kind of like, "Well, maybe it's..." I send them for cognitive behavioral therapy because I'm like, "Well, maybe this is also emotional that you're not," because they're like, "Well, nothing is getting better. My reflux is still terrible." This is actually practice changing. So if I have a patient who we've tried a bunch of different PPIs and they're not improving and they've done all the lifestyle changes, should I now be thinking I should genetically test them?

Dr. David Juurlink:

I think it's not a bad idea. So I would say that if a person's on a medication that both doctor and patient think is important and it's not working, one reason might be because of the patient's genetic makeup. And again, it's easy with something like codeine. It's tougher with a PPI because as you say, maybe the reason why the person still has reflux is because they're still eating and drinking things they maybe shouldn't or maybe they're timing their PPI dose incorrectly. But if someone’s got ongoing disabling reflux, maybe they just need a higher dose, and the way to easily check that is with their genotype.

Dr. Mojola Omole:

Interesting.

Dr. David Juurlink:

There's one more wrinkle worth mentioning here. It's that your genotype, meaning what your gene testing says, and your phenotype, which is how you behave, might be different. So let me give you an example using codeine. Let's imagine someone is on codeine for pain, for chronic pain, and they're taking, I don't know, 240 milligrams of codeine a day and they've been doing it for years and it's working for them. One could infer that they probably have the enzyme CYP2D6 that turns it into morphine.

What would happen if the doc put the patient on a medication that turns off CYP2D6? And we do this all the time. Bupropion turns it off. Celecoxib turns it off. So you can imagine a scenario where even though your genotype says you have active CYP2D6 or maybe even lots of it, you could in reality be a poor metabolizer because you're on another drug that just turns the enzyme off. And so this is one more little complexity here that I think is worth knowing about because sometimes what the genetic test says and what the patient or doctors see doesn't quite match up

Dr. Blair Bigham:

Now until we're doing universal genetic testing for drug genotypes. What is the path forward? We've been talking a lot about using race to sort of identify risk, and then that may be that triggering certain testing, but that's also controversial.

Dr. David Juurlink:

But it's intuitive too, right? So let's use carbamazepine and Stevens-Johnson and that HLA-B*1502 . So we know that particular HLA is vanishingly rare in people of Japanese descent, like 0.03%. It's very rare. Whereas in people of Han Chinese descent, it might be up in the order of, again, depends on the study, but on the order of let's say 5%. It's intuitively more appealing to undertake testing in people whose ethnicity puts them in a higher prevalence category. In other words, it makes more sense to test somebody in China than it would in Japan, or someone who's of Chinese descent as opposed to someone who's of Japanese descent.

So the other point to make is that we've talked about a couple of examples where I think it's reasonable to consider testing, but we still don't, for many of these tests, have a really good handle on what exactly the positive predictive and negative predictive values are. So we have more to learn about these things, so I don't want to give people the impression that they're bad doctors because they're not testing for these things. It's more about having an awareness and realizing that it might come into play at some point.

Dr. Mojola Omole:

So what advances are you expecting, let's say in the next decade, in terms of personalized medicine when we're talking about medications and effectiveness and I guess adverse events also?

Dr. David Juurlink:

I think we are going to see more and more patients being tested either reactively in response to a reaction or increasingly before drugs are started. And it'll be incumbent upon us to have some sense of how to approach this. So I'm aware of the fact that, for example, in Ontario, there is an initiative that's currently in place to help prescribers test patients and how to interpret the results of testing for various drugs.

So I can't say much more about it, but I'm pretty comfortable saying that within 6 or 12 months you'll be seeing stuff that a working group in Ontario has put out to advise people on how to go about doing this sort of testing and how to interpret the results when they come through. And I think you'll see more and more of that as time goes on, and I think it's going to lend itself to safer drug therapy.

I think one useful website that people might want to have in their armamentarium, if you type in CPIC, that's the Clinical Pharmacogenetics Implementation Consortium, into Google, it'll bring you to a website. It's got much more in it than most people want to read, but very well researched. It's kept up to date, and it's got all kinds of guidelines and gene drug pairs and publications for people who want to read more about this topic. It's a really great website.

Dr. Blair Bigham:

Very cool.

Dr. Mojola Omole:

This is amazing. Thank you so much.

Dr. Blair Bigham:

Yeah, thank you. This is great.

Dr. David Juurlink:

My pleasure, guys.

Dr. Mojola Omole:

Dr. David Juurlink, he's a staff internist and head of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto.

So Blair, what are your first impressions?

Dr. Blair Bigham:

This is fascinating to me. It seems pretty complicated in a way. Every time I try to get smart and order a test I don't normally order, I end up getting screwed when the results come back and I'm like, "Oh, I have no idea how to interpret this." You're either hoping for a really high result or a really low result. And so this just sort of adds to a little bit of uncertainty, but at the same time, it seems like it's so consequential for people.

Let's say you're prescribing a drug that you think is guideline directed medical therapy, and the next thing you know it just floats around their body but doesn't do anything. And so they're still at risk. It sort of puts all of our efforts in limbo. Why bother having doctors if we're just going to fall back on assuming that it's going to work in 93% of the population and for the other 7%, well, we'll just wait until their stent occludes or they'll have to get scoped because no one thought to double their PPI dose? It seems like it has real consequences for people, not just an insignificant 0.001% of the population, but we're talking about pretty remarkable numbers here.

Dr. Mojola Omole:

And I think part of that is because that's why we have continuing medical education is that a lot of this development is all very new. Talking about personalized medicine and genetic testing is all very new, but it is extremely consequential. I only remember P450. I didn't know about any other P470 or whatever else Dr. Juurlink was talking about.

So I do think that for us as physicians, we have to start, I never thought of that as my differential of when something is not working, "It's like, wait, could it be this?" And so now I'm going to start using that as part of my, for the things that we know, could this be part of the differential of why something is not working?

Dr. Blair Bigham:

And even if we don't have that capacity to keep all those different cytochrome things in our mind or understand all the genetic testing, or maybe people don't even have access to that genetic testing, in some places, at least we can be on that lookout for, "Oh, it's not working well, maybe I'll just double your dose and see what happens." Or, "Oh, you have a rash and a fever. This could be your allopurinol. This could be one of those drugs of concern that I have flagged in my mind." Maybe that's one of the best takeaways from today is that we just need to be thinking about it even though the execution of all these really fancy things aren't perfect yet.

All right. That's it for this week on the CMAJ Podcast. Be sure to like or share the podcast wherever it is that you download your audio. It goes a long way to helping us get the message out.

Dr. Mojola Omole:

I'm Mojola Omole.

Dr. Blair Bigham:

I'm Blair Bigham.

Dr. Mojola Omole:

And until next time, be well.