Using pharmacogenomics to personalise drug therapy

[Music] Welcome to the Australian Prescriber Podcast. An independent, no-nonsense podcast for busy health professionals.

As we aspire towards personalised medicine in the future, it makes sense to make much better use of the established tools that we already have. And when it comes to medicines and prescribing, well, pharmacogenomics is a big part of that. Pharmacogenomics, where we test for gene variants that might help us predict how our medicine will act, now has really strongly established science with the number of genes that are being shown to be clinically useful. These genes are ones which can affect pharmacokinetics, changing the amount of medicine that patients are exposed to at the site of action, or pharmacodynamics, influencing the response to the medicine. However, there's a lot of confusion about how this works in practice, where it's useful, and where we should be seeking to implement it.

Today I'm lucky to speak to Associate Professor Sophie Stocker, who's at the Sydney Pharmacy School at The University of Sydney and is co-chair of the National Pharmacogenomics Working Group of the Royal College of Pathologists of Australasia (RCPA). She has written an article in Australian Prescriber with one of her colleagues talking about how pharmacogenomics might be used in practice and how we might seek to implement it. Sophie, thank you so much for joining us today.

Thanks so much, David. Really looking forward to having this conversation with you.

Perhaps you can start by telling us, why do you think pharmacogenomics has been almost neglected in the way that most people practise?

Yeah, it's a really good question, David. I think it really boils down to one of the key issues being a lack of understanding of what pharmacogenomics is. There's a lot of genetic information being used in various aspects of healthcare. One of the most commonly used genetic testing is carrier screening when you fall pregnant in Australia, and we do carrier screening to identify whether an unborn child might be at risk of carrying a particular disease. And we also do genetic testing to identify someone's ancestry. And I think that really has caused this confusion about what pharmacogenomics is, and it really isn't anything to do with your ancestry and it won't tell you your risk of developing a disease. It will really just inform how effectively or efficiently your body metabolises or clears a medicine. And that can then impact drug exposure or it might inform whether you've got an increased risk of developing a hypersensitivity reaction to a medicine, and so it informs your risk of developing toxicity.

So maybe we could talk a little bit about the times when pharmacogenomics might be particularly useful. Talk me through when would we think about pre-emptive testing, concurrent testing, and so on.

So pre-emptive testing is essentially when you undergo pharmacogenomic testing before you've prescribed a medicine. This can be really useful for identifying these patients who might be at an increased susceptibility of developing these hypersensitivity or type B adverse drug reactions. These types of adverse drug reactions are unpredictable. They're not related to increased exposure, but they're really related to this interaction with the person's immune system. And we now know that there are particular HLA [human leucocyte antigen] markers that are associated with an increased risk of developing hypersensitivity reactions to a range of medicines. And essentially, if someone carries one of these HLA markers, then that particular medicine would be contraindicated and you'd need to select an alternative medicine.

So a nice example of pre-emptive testing is before you put someone on allopurinol used to treat gout, you might like to test whether they're positive for HLA-B*58:01. We know this particular HLA gene is associated with an increased risk of developing these hypersensitivity reactions.

And as many of you who have experienced a patient who's developed one of these hypersensitivity reactions, they really can be quite severe in the severe form and associated with a high risk of mortality and morbidity. So that's pre-emptive testing. It informs the selection of the most appropriate medicine for a patient. Then we can also do concurrent pharmacogenomic testing. So this is when you do the testing at the same time as when you initiate a particular therapy and it really informs whether that therapy should be ongoing because it's going to be the most effective agent for that particular patient or whether an alternative medicine may be more appropriate. So a nice example of concurrent pharmacogenomic testing would be a patient who's had a heart attack and has gone in to have a stent put in place or a percutaneous coronary intervention and they then would need to go onto antiplatelet therapy.

And we know that one of the more common antiplatelet therapies used is clopidogrel and it's activated or it's a prodrug and needs to be activated by CYP2C19, which is a drug-metabolising enzyme. And so you can imagine if you've got a genetic variant where that activity of CYP2C19 is reduced, then you're not going to produce as much of that active metabolite of clopidogrel, and that poses you at increased risk of developing a secondary ischaemic event, which is obviously something that we'd like to avoid. So sometimes this concurrent pharmacogenomic testing can really inform the most appropriate medicine for a patient, and that's particularly helpful for drugs used to prevent a particular condition from occurring or for prophylactic treatment.

Then finally we've got reactive pharmacogenomic testing. And this can be really useful to help in the diagnostic workup of a patient. So say you've got a patient and they don't seem to be responding as you would anticipate on a particular pharmacotherapy at that specific regimen, sometimes pharmacogenomic testing can help you decide whether a patient should be on an alternative medicine or whether you need to alter the dosing regimen of the current therapeutic treatment.

A nice example of this might be patients who are on warfarin and you are struggling to get their anticoagulation right? So you might do some pharmacogenomic testing and identify that they've got genetic variants in the drug-metabolising enzyme that metabolises warfarin so alters its exposure, or they might have a genetic variant in the warfarin target. So the protein in which the warfarin is targeting in order to elicit that anticoagulant effect. And that may tell you that a patient might be more sensitive to warfarin and therefore, a risk of over anticoagulation and bleeding, therefore switching them to an alternative oral anticoagulant might be most appropriate.

It seems like there'd be a lot of patients who might benefit from this. A lot of people have adverse drug reactions. Certainly a lot of people are at risk of adverse drug reactions and there are a lot of people who are getting suboptimal medicines dosing. You would imagine with all the genetic testing that we've got access to that maybe we might be able to do pharmacogenomics for everyone, but that's not really the case, is it? How do we get from that to things that we might use in clinic?

I think this is a really good question, David, and it's not one that I propose to have the answer to, and it's unlikely to be a very simple single-approach solution. But there are groups around Australia working at repurposing genetic information that might've been collected for an alternative application, and then from that genetic test actually pulling out the pharmacogenomic genes and then reinterpreting that information in the context of medication management and perhaps the initiation of new pharmacotherapy. I think that's really a smart way at trying to use genetic information we already have available for patients and reusing that for another purpose.

And then of course, there is also a group of patients where they haven't undergone genetic testing in the past, and therefore if they're being initiated or it's thought that they might benefit from a particular pharmacotherapeutic agent for which pharmacogenomic testing is indicated, then perhaps they may benefit from this type of testing.

So right now we've got a much smaller group of indications where we've got a specific gene that we're testing for, a specific medicine in mind, and those are the ones which we know can actually help us with patients right today. Isn't that right?

So the RCPA pharmacogenomics indications is heavily based on the evidence that we have to date. And we've grouped medicines into 3 categories, those for which pharmacogenomic testing is recommended, these are medicines where we have a wealth of evidence to show that if you do pharmacogenomic testing, you can improve patient outcomes. And for most of these gene–drug pairs, we've also shown that pharmacogenomic testing is effective from a cost standpoint, so either cost neutral or cost saving in various healthcare settings. And then we've got groups of medicines and genes for which pharmacogenomic testing could be considered. Here, the risk to the patient may not be life threatening, and we have a growing body of evidence to show that pharmacogenomic testing can improve patient outcomes. And depending upon the clinical testing, a healthcare professional might consider doing pharmacogenomic testing to just help inform their decision and personalise therapy a bit more.

And then we've got a group of medicines for which pharmacogenomic testing, there's currently a lack of consensus. That doesn't necessarily mean that there isn't a strong association between the genetic variant and the influencing response to that medicine, but it just hasn't yet reached that threshold which would put it into the consider category. This may be for medicines which are new on to the market or where we are currently in the process of gathering evidence of clinical utility.

So going back to that first category for clinic today, what are the big-ticket items that we've got there? What are we looking for?

A lot of the medicines that are in the recommended category are those where we have a small proportion of patients who develop these hypersensitivity reactions. And this is because there's not a lot of other clinical data that you can use to really gauge the risk that your patient might have of developing these hypersensitivity reactions if you don't have the genetic test. And so we've got drugs like abacavir, allopurinol, carbamazepine, oxcarbazepine and phenytoin, where this pharmacogenomic testing can really help you identify if your patient is going to have an increased risk of developing these hypersensitivity reactions.

So given that these hypersensitivity reactions can be life threatening in the severe form, these are the patients we obviously need to identify as early on in the piece, ideally before prescribing that medicine, in order to avoid that event from occurring in the first place and prevent that patient harm.

It's exciting to think that we might be able to do better by patients in these specific situations. I'm guessing it's not all as straightforward as that, despite the wealth of evidence that we've got. There are probably times when it's more appropriate, less appropriate, and there might be times when things can go wrong. Can you talk us through some of those challenges and pitfalls that we have with pharmacogenomic testing?

I think it's true that it's a little bit more complex than a binary outcome. So the drugs which are associated with hypersensitivity reactions where we're looking for a HLA marker, there, it's a little simpler. You either carry the risk genetic variant or you don't. And if you carry the genetic variant that's associated with an increased risk, then that medicine would be contraindicated. But for a lot of the drug-metabolising enzymes, there is complexity, particularly in the setting of polypharmacy when you're interpreting that pharmacogenomic test. You can imagine that someone might have a genetic variant which reduces an enzyme activity and, therefore, changes drug exposure to a particular medicine. But if that patient is also on a concomitant medication, so another medication, they're taking more than one medicine, and that second medication actually also influences that particular enzyme's activity, particularly if it has attenuating or mitigating effects, then that makes it quite challenging to interpret that pharmacogenomic test result.

We actually call that process phenoconversion, and essentially, that means if someone is carrying a genetic variant, which means they're, for example a 2D6 poor metaboliser, so they have low activity of CYP2D6, but they might be taking another medicine which is a CYP2D6 inducer, and that will increase their 2D6 activity, and so their phenotype or their response to the medicine may not be characteristic of their genotype.

And I think this is one of the complexities about interpreting pharmacogenomic tests, particularly in a setting of polypharmacy. And it's a space where I'd really strongly advocate that healthcare professionals seek counsel or guidance from pharmacists, medicines experts, or clinical pharmacologists to help guide them through the interpretation process and recommendations to their patients.

It's always the case that it's good to have the right kind of expertise to walk you through complex situations. Pharmacogenomics is clearly no different. You just can't read the line off a page and then know exactly what's going to happen.

I want to get back to the complexities of the system in a little bit because clearly, that's a challenge, as well. But maybe you can tell us a little bit about how we might do this testing in practice, what kind of samples we need, and what the funding environment looks like in Australia right now to get this done.

I think the pharmacogenomic testing itself is relatively simple. So you can either use a blood test, but you can also use buccal swab, so cheek cells, that may be much more appropriate, particularly in a paediatric population or in a rural remote setting where patients may not have ready access to a pathology collection centre for the blood collection. These samples, when they're collected either blood or cheek cells or buccal cells, it's relatively easy to transport the samples. DNA is extremely stable. We have been able to collect genetic informational DNA from mammoths. It's a really stable compound, which is a huge advantage given the scale of the Australian landscape. So you can transport those samples just at room temperature. For the cheek swabs, you can actually just put them in the regular post to get them to the pathology service.

This, of course, sounds like it costs money. I can imagine, as well, though, there's a bit of consideration about how you get this funded and what kind of testing comes at what kind of cost. All of this testing, of course, is heavily accredited so that it's consistent wherever you get it done. How do we navigate this? What's funded, what's not? How much do things cost?

So the cost of the test will depend on whether you're getting a single-gene or a targeted-gene test, or if you're getting a panel of genes. So that might include 9 to 12 different genes. So if you're getting a panel pharmacogenomic test that includes those multiple genes, it'll cost the patient around about $150 to $200. That panel testing approach currently does not attract a Medicare rebate, so that cost would be borne by the patient or the institution. For targeted tests, they're usually between $50 and $200 depending upon what gene you're testing. And again, typically, these are funded by the patient or the institution. At the moment, we've got TPMT [thiopurine methyltransferase] attracts a Medicare rebate, so that's for patients who are being treated with azathioprine, mercaptopurine or thioguanine. HLA-B*57:01 also attracts a Medicare rebate, and that should be done prior to prescribing abacavir.

And excitingly, we've just had a new gene test attract Medicare rebate. DPYD [dihydropyrimidine dehydrogenase] has attracted an MBS [Medicare Benefits Schedule] rebate, and that's going to be really helpful for patients receiving 5-fluorouracil and capecitabine. So that rebate will come into effect on the 1st of November, 2025. And we're really looking forward to the impact this is going to have on reducing toxicity to these chemotherapeutics and ensuring that we have adequate treatment response while avoiding, as much as possible, that patient harm.

Really great to see that kind of progress and that recognition, but I guess it must be harder across the breadth of things to be able to try and get the rest of this into practice. And even when Medicare funded, gene tests are probably hard to get to the people who need them. How has this been in terms of implementing in practice? Can we improve the way that pharmacogenomic testing is delivered on a community-wide basis?

Yeah, I think this is a really important issue to untangle. We need to be able to implement it in an approach that is suitable for a range of healthcare sectors, as well as patient populations. Therefore, the solutions are going to vary and implementation and models of care are going to vary. There'll be some that need to be implemented in the acute care setting in hospitals, and there'll be other pharmacogenomic tests that may be more appropriate to be implemented in the community setting. So this may be where our pharmacists and GPs really take the lead in selecting and identifying patients that might benefit from pharmacogenomic testing. So it'll really depend upon which patient population you're treating.

But I think there's a variety of people that are really trying to identify how we integrate this testing in our everyday workflows and to ensure that we can implement it easily and efficiently into current practices. And I think this evidence will come to peer-reviewed literature and also be disseminated amongst healthcare practices and professionals as we learn more about how to implement this type of testing.

It must be hard with the data itself. People get very nervous about any genetic data, but then the process of data sharing and interoperability between complex systems across our siloed medical record system in general, trying to make sure that we don't duplicate testing, that we don't miss telling the right people about test results when they're relevant. That must be a real challenge.

Yeah, I think this is a huge challenge with this type of information. Ideally, this pharmacogenomic testing, particularly if you do a panel test, should be the type of information that sits with your record throughout life as you potentially develop certain conditions, and therefore, require medicines for which this information is useful. Somehow we need to identify ways that this information is readily available to the patient themselves, but also their wider healthcare community, and that it can be accessed at various points throughout their life journey. So it needs to be available to general practitioners, to pharmacists, and it needs to be available to hospital clinicians. And I think that remains a challenge. There's been advocates to have this information uploaded to MyHealthRecord to help with that interoperability, but there definitely will need to be concerted and well-designed approaches to try and ensure the interoperability of this type of information.

Looking elsewhere in the world, how have other countries handled this? There's been some very high-tech approaches, but also some very low-tech approaches. So for example, in Europe, one of the largest studies looking at implementing pharmacogenomics has used, essentially, a little credit card that goes in people's wallets and has a little QR code on it, and anyone who has access to that credit card can scan the QR code and find that information. It may not always be a high-tech solution to this problem, but problem certainly something that we need to work through that ensure that it's appropriate for the Australian healthcare setting.

Well, high tech, low tech, if we can get to where we need to go to try and deliver testing that's going to make a difference to our patients, all the better. Sophie, thank you so much for talking to us today on the Australian Prescriber Podcast.

My pleasure, David. It's been a really lovely conversation.

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Sophie Stocker is the lead investigator of a Gilead-funded trial investigating the use of pharmacogenomics to deliver individualised therapy on antifungal drugs. She's also leading a trial evaluating implementation of pharmacogenomics in aged care. Sophie received complimentary registration to the 2024 Pharmaceutical Society of Australia Conference and was invited to speak on pharmacogenomics. Sophie is a co-chair of the Royal College of Pathologists of Australia Pharmacogenomics Working Group, which developed the RCPA's list of indications for pharmacogenomic testing in Australia.

And I'm on the Drug Utilisation Subcommittee of the Pharmaceutical Benefits Advisory Committee. I'm David Liew, and thanks once again for joining us on the Australian Prescriber Podcast.