Clopidogrel is commonly prescribed for secondary prevention of ACS. The drug has to be converted to its active metabolite before it can take effect (as a P2Y12 platelet inhibitor). This requires the hepatic enzyme cytochrome P450 2C19 (CYP2C19) – an enzyme that is subject to genetic polymorphism. The presence of one or more loss-of-function (LOF) alleles of CYP2C19 results in ‘poor metabolisers’ and ‘intermediate metabolisers’ who are unable to activate clopidogrel.

This study set out to determine the prevalence of common CYP2C19 polymorphisms in a British–South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel.

DNA samples from more than 44,000 volunteers were analysed. This group had a high prevalence (57%) of intermediate or poor CYP2C19 metabolisers, with at least one LOF CYP2C19 allele.  Of note, the prevalence of poor metabolisers carrying two CYP2C19 LOF alleles was 13%.  Previously reported proportions for European and Central/South Asian populations have been 2.4% and 8.2%, respectively.

Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; P = 0.019). In fact, there was a clear gradient of increased risk of recurrent myocardial infarction with increased LOF burden.

The results of this study underline the potential importance of pharmacogenetic (PGx) testing so that the genotype is known before the prescription is issued and adjustments can be made. The alternative would be to prescribe non-CYP2C19 dependent platelet inhibitors such as prasugrel or ticagrelor for everyone but the costs may be too great.

Actionable drug-genome interactions are not uncommon and routine PGx testing services have been advocated  commenting on the findings Professor David Wright said:

“This is why all services need to be delivered in a culturally competent manner. PGx evidence is biased towards the white European population and may not translate to other populations. If the profession is to assume responsibility for PGx testing it will need to ensure that all patient groups are aware of its potential limitations when their DNA is taken. I would hope that any software providing guidance following PGx testing will be routinely updated with such evidence as it would be impossible for any individual to be able to remember these differences.”

Professor Wright (University of Leicester) leads a research team focused on design and implementation of routine pharmacogenomics (PGx) services in community pharmacy.

Reference

Magavern E, Jacobs B, Warren H, et al. CYP2C19 Genotype Prevalence and Association With Recurrent Myocardial Infarction in British–South Asians Treated With Clopidogrel. JACC Adv. null2023, 0 (0) .https://doi.org/10.1016/j.jacadv.2023.100573

The added value of pharmacogenomics to prescribing

Pharmacogenetic information allows clinicians to identify people who handle drugs differently and may therefore be at risk of over- or underdosing of certain medicines. This means that prescribers can ‘get it right first time’ – reducing the risk of waste as well as reducing the risk of exposing the patient to harm due to over- or under-dosing.

One example of the way on which pharmacogenetic information can guide prescribing is the identification of DPD deficiency resulting from a mutation in the DPYD gene (which codes for the enzyme dihydropyrimidine dehydrogenase (DPD). DPD is involved in the metabolism of fluoropyrimidine drugs – e.g. 5-fluorouracil and capecitabine. DPD deficiency is associated with increased toxicity from such drugs. Pre-treatment testing and dose adjustment is now the standard of care.

How does pharmacogenomics work in day-to-day practice?

A number of examples illustrate the way that pharmacogenetic testing can be used to improve the safe and effective use of drugs.

A mitochondrial mutation – m.1555A>G – is linked to increased susceptibility to deafness if treated with aminoglycosides.  “When that’s associated with a maternal history of deafness then the risk goes up even further”, says Dr Onatade. Pre-treatment testing is advised and there is even a point-of-care test available for neonates.

Genetic variation can lead to reduced activity of the enzymes TPMT (thiopurine methyltransferase) and NUDT15 (nudix-type motif 15) and increased toxicity of purine analogues e.g.  6-mercaptopurine and 6-thioguanine.

Pharmacogenetic testing in relation to psychotropic drugs is less well-developed. Currently there is much research in this area; one important question is whether routine testing and the identification of fast- and slow-metabolisers will actually make a difference to outcomes.

The challenges of developing pharmacogenomic services

The PREPARE study demonstrated that there was a significantly reduced likelihood of developing adverse reactions if people were tested for 12 specific genes in advance of treatment. “There seems to be a really good case for introducing some routine pharmacogenetic testing for these commonly-used drugs into normal treatment”, says Dr Onatade.

Now the NHS needs to build the infrastructure to support the implementation of pharmacogenomic services. “Whenever I speak to other clinicians, other …. healthcare professionals, they’re really clear that leadership for pharmacogenomics must come from pharmacy”, says Dr Onatade.

Two key challenges now are, first, education and training for pharmacists to ensure that they are familiar with the topic and able to advise health care professionals and patients appropriately and, second, informatics structure and processes to ensure that the genetic information is available when required but is securely protected.

About Raliat Onatade

Raliat Onatade holds three positions:

• Chief Pharmacist for Northeast London Integrated Care System
• Group Chief Pharmacist for Bart’s Health NHS trust also in East London
• Chief Pharmacist for North Thames Genomic Medicines Service Alliance

Dr Onatade’s EAHP keynote presentation, Personalised medicine – opportunities for hospital pharmacists in clinical practice can be viewed at: https://events.eahp.eu/cmGateway/vimeoplayer.html?vimeoId=810496208

Read and watch the full series on our website or on YouTube.

The PREPARE (PREemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions) study assessed the impact of pre-emptive pharmacogenomic testing on adverse event incidence in a randomised, cross-over study.  A 12-gene pharmacogenetic panel was used to identify actionable gene variants and this was used to guide prescribing in the ‘test’ arm; the standard care arm did not receive pharmacogenomic testing.

“What they demonstrated was that there was a significantly reduced likelihood [of developing adverse reactions], if people were tested for these specific genes ahead of being treated with these medicines. So, what this says is that there seems to be a really good case for introducing some routine pharmacogenetic testing for these commonly-used drugs into normal treatment”, says Dr Onatade.

Implementation

The NHS is making huge strides towards the implementation of genomic services.  The ambition for the NHS to become the first health service in the world to introduce genomic medicine into the mainstream of healthcare treatment. “Pharmacogenomics is absolutely fundamental to this as a branch of genomic medicine – so there’s a lot of work at the moment in terms of building the infrastructure. …….. So, we need to make sure there’s enough capacity in our laboratories in order to deliver these tests.  There’s a question about whether or not, for example, people should be tested from birth or only when there’s a particular drug that’s needed – so lots of questions still to be still to be answered. I think that for pharmacogenomics in particular, then whenever I speak to other clinicians, other …. healthcare professionals, they’re really clear that leadership for pharmacogenomics must come from pharmacy – and I think that there’s a lot that we can do because we understand the medicines”, says Dr Onatade.

There is a need for education and training to ensure widespread understanding of the fundamentals of genomic medicine. Pharmacists, who already have  experience of introducing new medicines into the health system, introducing new pathways, writing guidelines and talking to people about their medicines will now have to add genetic counselling to their repertoires, she suggests.

Another important aspect of these developments is understanding the cultural sensitivities – the importance of people’s values and beliefs when it comes to genomics and genomic medicine – “because it’s not quite the same thing as saying ‘we need to test your renal function before you we provide this medicine’”.

Dr Onatade explains: “What we really need to do is to embrace this because it’s not actually the future, it’s here now.  It’s just going to get bigger and bigger and bigger and so we all need to embrace it and to understand the value of this and to be able to talk about it as [part of] normal standard care so that when people come to ask us then we actually have an answer to give to them. That really is what we’re trying to do within the Genomic Medicines Service Alliance – to really spread the knowledge, spread the training and encourage people to be familiar with pharmacogenomics and genomic medicine in general”.

When it comes to training there has been a drive to focus on newly qualified pharmacists and new entrants to the profession but pharmacists who are currently in practice also need to acquire a good understanding of pharmacogenomics because it is already becoming part of care –. “If you focus just on students and undergraduate teaching then we’ll be five years behind”, emphasises Dr Onatade.

Challenges

There are numerous challenges in the implementation of routine pharmacogenomic services; Dr Onatade identifies two critical aspects:

First – in order to be able to provide the correct and appropriate treatment for patients, pharmacists need to be able to interpret the pharmacogenetic reports and this calls for a basic level of understanding of some fundamental concepts. “That really is the key thing that you need to know so that when you see a report then you could really can understand what it’s telling you in order to advise the clinician or advise the patient on what it actually means and the implications for further treatment. – These reports can look quite daunting when you first look at them but actually after a while you begin to understand and pick out the really relevant and important parts to speak to the patients about”, she says.

Second – the informatics structure and processes need to be agreed. “What format is the information in? How does that information get into our patient record? How is that information shared? ….. How is it protected – bearing in mind that the information is about a person’s genetics data and stays with them for life. So, again it’s another consideration around making sure that the information is available but is also held very confidentially, but people can use it when needed at any point in our patient’s treatment throughout their whole lives”, says Dr Onatade.

About Raliat Onatade

Raliat Onatade holds three positions:

• Chief Pharmacist for Northeast London Integrated Care System
• Group Chief Pharmacist for Bart’s Health NHS trust also in East London
• Chief Pharmacist for North Thames Genomics Medicine Service Alliance

Dr Onatade’s EAHP keynote presentation can be viewed at https://events.eahp.eu/cmGateway/vimeoplayer.html?vimeoId=810496208

Read and watch the full series on our website or on YouTube.

Mitochondrial mutation

The mitochondrial mutation m.1555A>G is often associated with maternally-transmitted deafness. People who carry this mutation are more likely to develop deafness if treated with aminoglycosides even if not exposed to toxic levels of the drugs. “When that’s associated with a maternal history of deafness then the risk goes up even further”, adds Dr Onatade. In the UK, the Medicines and Healthcare Products Regulatory Agency (MHRA) advises pre-treatment testing of patients who are likely to receive repeated courses of aminoglycosides, such as individuals with cystic fibrosis. “Certainly, if we have somebody with aminoglycoside-related toxicity then the recommendation is to test for this mutation so that we can understand whether or not they’ve got that increased sensitivity to it”, says Dr Onatade.

“Neonates are also tested for this and there is actually now a point-of-care test that is available to test neonates – so then that can be done before treatment is started”, she adds. At present, the point-of-care test is only validated for neonates. The test for adults is laboratory-based and this takes several days to turn round and so it may be necessary to give one course of treatment before the results are known.

TPMT and NUDT15

Thiopurine methyltransferase (TPMT) and nudix (nucleoside diphosphate-linked moiety)-type motif 15) NUDT15 are both enzymes involved in the metabolism of purine analogue drugs such as 6-mercaptopurine and 6-thioguanine. Variants of the genes that code for the enzymes can result in reduced enzyme activity and increased toxicity of the drugs. The NHS has recently agreed to commission these tests but only when these drugs are used for the treatment of acute lymphoblastic leukaemia. “That’s because before any test is commissioned and therefore paid for by the NHS, there has to be a very rigorous assessment of the evidence and of the value for money [and] the cost-effectiveness. However, they are still used in many other conditions where we treat with these drugs – so nobody’s missing out”, she adds.

Pharmacogenomic testing for CNS drugs

“The use of the pharmacogenetic testing in mental health or [in relation to] psychotropic drugs is really interesting. There is no officially-commissioned genetic test but as a general rule what we’re looking for is whether or not somebody metabolises particular drugs either very slowly or very quickly. …. For example, if somebody is an ultra-rapid metaboliser then they may well need a higher dose and if they are a particularly slow metaboliser then they might need a lower dose in order to not have side effects”, explains Dr Onatade.  The importance of this is that “even now, after decades and decades of having psychotropic drugs available to us therapy is often still very much ‘try it out and see’”, she adds. Knowing in advance if someone was likely to be more or less sensitive to the effects of a drug would allow greater precision in treatment. Currently there is much research in this area; one important question is whether routine testing will actually make a difference to outcomes.  The possibility of targeting ortailoring therapy to someone’s drug metabolic capacity would be a huge advance, she says.

About Raliat Onatade

Raliat Onatade holds three positions:

• Chief Pharmacist for Northeast London Integrated Care System
• Group Chief Pharmacist for Bart’s Health NHS trust also in East London
• Chief Pharmacist for North Thames Genomics Medicine Service Alliance

Dr Onatade’s EAHP keynote presentation can be viewed at https://events.eahp.eu/cmGateway/vimeoplayer.html?vimeoId=810496208

Read and watch the full series on our website or on YouTube.

Dr Onatade’s role in the North Thames Genomic Medicines Service Alliance is concerned with the strategic direction of pharmacy and pharmacogenomics in North Thames and ensuring that it is linked with the national agenda for genomic medicines services.

The terms ‘personalised medicine’ and ‘precision medicine’ are often used interchangeably but they are different. Personalised medicine considers the genetic makeup of an individual together with their values, social context, behaviours and attitudes and then tailors the treatment and care on that basis. Precision medicine is usually defined as a model for healthcare delivery which takes into account data, information and analytics. “The outcome really is by and large the same whether it’s ‘personalised’ or ‘precision’ in that it’s tailored to the care of that individual”, explains Dr Onatade.

Pharmacogenetic prescribing guidance

Pharmacogenetic information allows clinicians to identify people who handle drugs differently and may therefore be at risk of over- or underdosing of certain medicines. It “can also help us be more efficient with our dosing strategies because you’ll know if somebody has got a specific genetic mutation which might make them either more sensitive or less sensitive to the effects of a medicine”, says Dr Onatade. Moreover, “when you think about all of that in the round it can also help with, for example, reducing the risk of polypharmacy because you can make sure that you’re getting it right first time – reducing the risk of waste as well as reducing the risk of exposure [of] your patient to harm due to a medicine which they may be more sensitive to”, she adds.

Precision diagnostics

Another term that is frequently seen is ‘precision diagnostics’.  This refers to the diagnosis of specific diseases on the basis of, for example, pharmacogenetic analyses. “Precision diagnostics really drives precision medicine …….and cancer is a really good example – where you can actually diagnose the genetic cause of a tumour, for example, then you can tailor your therapeutic treatment to that genetic cause”, explains Dr Onatade.

Dihydropyrimidine dehydrogenase (DPD) deficiency  

“We’ve been working on the use of DPD- and DPYD-deficiency for a long time it’s only very recently that it’s become very mainstream”, says Dr Onatade.  DPD is an enzyme that is involved in the metabolism of fluoropyrimidine drugs – two commonly-used examples are 5-fluorouracil and capecitabine. “DPYD is the gene that codes for the enzyme. Now, if you have insufficient DPD caused by a mutation in the DPYD gene you are more susceptible to the toxic effects of these chemotherapeutic drugs – and they can be very, very toxic”, says Dr Onatade. For this reason, patients should be checked for DPYD mutations before starting treatment with one of these drugs. Hospital pharmacists have two important functions here – the first is to check that the patient has been tested before treatment starts and the second is to provide advice on the change in therapy or dosing so that patients are not at risk of toxic side effects.

Dr Onatade comments: “This genetic variation has been well-known within cancer and oncology circles for a very long time and so for a very long time most oncology centres were actually testing for that before it became widely known. What’s happened [more recently] is that NHS England have now mandated the introduction of the test, so now it is an accepted standard of care.”

About Raliat Onatade

Raliat Onatade holds three positions:

• Chief Pharmacist for Northeast London Integrated Care System
• Group Chief Pharmacist for Bart’s Health NHS trust also in East London
• Chief Pharmacist for North Thames Genomic Medicines Service Alliance

Dr Onatade’s EAHP keynote presentation can be viewed at: https://events.eahp.eu/cmGateway/vimeoplayer.html?vimeoId=810496208

Read and watch the full series on our website or on YouTube.