Federica Santoro 0:15

Welcome to Drug Safety Matters, a podcast by Uppsala Monitoring Center, where we explore current issues in pharmacovigilance and patient safety. Medicines are manufactured with extraordinary precision, so that each and every pill, capsule, or vial is as identical as can be. The same, however, cannot be said for us humans. People can vary greatly in their response to medicines, and one of the reasons for it is their genes. I'm your host, Federica Santoro, and my guest today is my colleague Chun Ying Yu, medical doctor and senior pharmacovigilance expert at Uppsala Monitoring Center. Ying has long been fascinated by pharmacogenomics, the science of how genetic variation influences the response to drugs. So I took the opportunity to ask her about past, present, and future developments in the field. Hi Ying and welcome to Drug Safety Matters. Now you should know that on this podcast we love words that are difficult to pronounce, and usually it's pharmacovigilance we deal with. But for today's episode, we've opted for another tongue twister, pharmacogenomics.

SPEAKER_00 1:48

What is it? Well, pharmacogenomics is the study of the role of the genome in drug response. You may have heard several definitions. One of them is called pharmacogenetics, which is a study of inter-individual variation in DNA sequence related to drug disposition, metabolism, or drug action that can influence drug response. The other definition is pharmacogenomics, which is defined more broadly as the application of genomic technologies to elucidate disease, susceptibility, drug discovery, pharmacological function, drug disposition, and therapeutic response. But these terms are usually used interchangeably. So if you look at its name, which is the combination of pharmaco, meaning pharmacology, and genomics, which is the study of the genetic material such as DNA. So there are two main areas in pharmacology. One is the drug action, so-called pharmacodynamics, which is about what the drug does for a human body. And another is drug concentration, or that affect the amount of drugs in the body after drug intake, so-called pharmacokinetics, which is about absorption, distribution, metabolism, and excretion of the drugs from the body. And it's what the human body does for the drug. And both pharmacokinetics and pharmacodynamics can be affected by genes.

Federica Santoro 3:31

Okay, so we're basically studying people's genetic makeup and trying to understand how that affects people's response to drugs. But how do you do that exactly? And why does it matter for pharmacovigilance?

SPEAKER_00 3:46

Well, pharmacogenomics analyzes how the genetic makeup, the genetic material of a person affects their response to drugs. So to say, yeah, the pharmacokinetics and pharmacodynamics. In order to find the association between a genomic material and drug response, you may, for example, want to compare the genome of a patient with the adverse drug reaction with those without adverse drug reaction and to find a method to test this. One of the methods is a genotype to use genomic biomarkers. And there are biomarkers for drug metabolizing enzyme genes, or to test the risk status of a person. For example, a person with immune-related adverse drug reactions like the HLA human leukocyte antigene complex. Assignment of whether a person has a specific genetic variant or not is what a pharmacogenomic is doing. And you collect DNA from blood or saliva or other material from the body, and you look at the genes directly. But the predictability may vary. For the drug metabolizing enzyme, people with the same genotype could have variations due to other factors, for example, the organ function, other medications that are used at the same time. It can predict drug response in an ideal situation or to different extent, but it's not always 100%. For the phenotype, that is the appearance of observable nature of individual, for example, enzyme activity, drug levels after drug intake. And it's one method for phenotyping is the measure of drug and its metabolite, and calculate the ratio. The higher the metabolic ratio is, the lower the enzyme activity will be. So for drug metabolizing enzyme, the genotyping or phenotyping testing, we divide people into different groups according to, for example, the capacity to break down the medicine. You may have a normal metabolism called extensive metabolizes. You may have poor metabolizes that person have both genes, one gene from a mother, one gene from a father, both genes are virants. And you may have intermediate metabolism, that is a heterozygote, or carrying genes for lower enzyme activity. And then you have the ultra-rapid metabolism, that is a gene duplication. You have sometimes multiple gene duplication. So your question on why does it matter for pharmacovigilance? You know, we want to maximize drug response and minimize adverse events. And this can be done by using the individual's genetic profile, by using genotyping or phenotyping method to select right patients for the right disease and right drug with the right dose. I can tell you a story how this can be done. Many years ago, a woman with a depression was prescribed a normal dose of antidepressant notriptaline, 100 to 150 milligrams per day. There was no effect. The dose was increased to 300 milligrams per day and still had very low drug levels in the body, was questioned whether the patient has taken the drug. The patient was found then to be an ultra-rapid metabolizer and had to be treated with 500 milligram daily notryptalin, which is three to five times the recommended dose to attain therapeutic blood levels. So pharmacovigilance is about drug safety, it's about adverse drug effects related to the collection, detection, assessment, monitoring, and prevention of adverse drug reactions. And this includes lack of efficacy as well for severe diseases.

Federica Santoro 8:09

But where did it all begin? I'd like to take a little walk down memory lane with you and talk a little bit about the origins of the science. So this idea that one could predict people's response to drugs by looking at their genes, when did that develop and how?

SPEAKER_00 8:31

Well, you find variability and outliers. When you give the same dose of a drug to different people, the response will be different, either due to variability at the target of the drug, example the receptors, or due to variability in the amount of active substance in the body. This is one thing. Another thing is that people will have adverse drug reactions of the target, not related to the drug effect, but maybe related to the immune system. And the concept that genetic factors can be responsible for different drug response in some patients evolved in the 1950s. At that time, it was demonstrated that inherited deficiency of the enzyme called glucose 6 phosphate dehydrogenase, G6PD, was responsible for the severe adverse reaction hemolysis, which is a red blood cell breakdown leading to anemia, red blood cell level in some patients after taking the antimalaria drug, primaquine. Primaquine is an effective drug, but due to the very serious adverse reaction, the drug is not recommended for use in people with a deficiency with this enzyme G6PDE. And also in the 1970s, another important enzyme was discovered to be polymorphic with genetic variants, which is debrisoquine dehydrogenase, the enzyme that breaks down the drug molecule debrisquine. Do you want me to tell you a story? Do that. A group of researchers in the UK studied debrisquine, the antihypertensive drug. A few percent of the healthy volunteers, including the researchers and professors themselves, developed overdose reaction despite the same dose was used for everyone. It was found that these overdosed people with very low blood pressure had a very high blood concentration of debrisoquine and a very low concentration of the metabolite for hydroxydibrisoquine. And this led to the discovery of the genetic variance or polymorphism in a very important drug metabolizing enzyme now called CYP2D6, and that metabolizes a large amount of clinically commonly used medicines. So this is about variability and outliers.

Federica Santoro 11:07

And do we have an idea of how many adverse drug reactions have a genetic basis?

SPEAKER_00 11:13

Good question, but hard to answer. Depending on the drug and also on ethnic factors, the genetic factors have been suggested to account for 20 to 95% of the variability in drug disposition, leading to a so-called type A adverse drug reaction, which is related to the pharmacology. But for the type B serious ADRs that might be immunological reactions, it's more rare. Because if very serious ADRs are common, the drug may not have been approved. But these type B reactions, they may be more dramatic with a serious consequence for the patient and also for the drug as well. Because people are more worried about serious reactions and may cause media attention as well, and even leading to drug withdrawal from a market.

Federica Santoro 12:11

Now the next question comes actually from one of our listeners because we asked people on social media to send us questions on pharmacogenomics for you. So here's the first one. Nicole wonders does pharmacogenomics translate to a reduced burden of side effects? So in other words, what have been some of the successes so far?

SPEAKER_00 12:36

Well, pharmacogenomics, with the help of using genomic biomarker, could do several things. One is it could identify drugs with a large variability in patients taking the drug and provide right recommendations on the use of the product with appropriate dosing recommendations. And a good example is a recent approved drug called Ligglostat, which is indicated in the rare disease. And this drug should be dosed according to genotype of SIP2D6. And the second thing the pharmacogenomic biomarker use could be applied to screen patients before starting treatment. You could identify patients at risk for lack of efficacy or at risk status for toxicity and prevent or minimize the risk. For example, change the drug or drug therapy regime. And one example is the anti-HIV drug, abacavir. In patients who carry a special gene variant called HLAB5701, these people will be at high risk for hypersensitivity. And due to the development of this biomarker, this association of this HLA allele and the hypersensitivity, the drug could be saved by giving the drug only to people who are not carrier of this virus. And also during treatment can explain why the drugs not work in some patients and to give advice to monitor the patients and to give another drug, for example, and to choose right doses sometimes. Sometimes it's important with interesthnic differences. One example is cabamezepine. It's an old drug. It's commonly used for epileptic patients. But this drug has a very serious adverse drug reaction in the skin. And this is particularly important for Chinese patients. There is an HLA allele. If you have this allele, your risk for Stephen Johnson disease, for example, will be increased many times. And the labeling was changed to screen Chinese ancestry patients. And by avoiding kapameting in the carry of this allele, it was shown the usefulness of this biomarker in a large study where no cases of a serious adverse skin reaction was found. So this is one of the very good examples of the usefulness of the genomic biomarker in a special ethnic population. And another example that is useful is for the SIP 2D6 enzyme, as we mentioned, where haloperidol is an anti-schizophrenia drug. Also in Chinese population, it was found that the Chinese had about 50% higher plasma concentration than the US non-Asian patients. So when prescribing haloperidol to patients of Asian ancestry, physicians should consider that higher than expected plasma haloperidol concentration and an increased sensitivity to haloperidol may occur. And this was already published in the 1980s.

Federica Santoro 16:23

So that's quite a few success stories. I hope Nicole had her question answered. Now I'm glad you brought up the point of ethnic differences, because that'll lead nicely into our next question, which is also from our listeners. And this time it's two of our social media followers, Alexandra and Nikita, who are both interested in the issue of ethnic diversity in clinical trials. All the stories you've described so far have one thing in common. The effects of genetic variance on people's response to drugs was discovered only after the medicine had been placed on the market. But wouldn't it be better if we could learn this information in advance? And so Alexandra and Nikita argue that a cost-effective way to gather pharmacogenetic information before the medicine is placed on the market would be to increase diversity in clinical trials. The problem is that even though trials nowadays are run in lots of different countries, racial and ethnic minorities continue to be severely underrepresented. So their question is what needs to happen for that to change? How do we increase ethnic diversity in trials?

SPEAKER_00 17:50

Well, trials are being done in more countries nowadays, and this is because of two factors. The first one is that there is a growing shortage of treatment naive patients. Many patients in the wealthy countries like the United States or Western Europe, they have access to medications outside the clinical trial setting. So there is a shortage of people with a particular condition who are not already taking medications in these wealthy countries. And another factor is the economic one, the lower cost of hosting clinical trials in Eastern Europe and Asia. But we know that it's not always practical to conduct drug trials in every patient population in the world. So I think one approach is to choose a particular place and increase the participants in that place, for example, Chinese in China. And the number seems increasing already. Another approach is to conduct sort of bridging studies, ethnol bridging studies. Here, a drug that has been assessed in a major clinical trial in Western countries is then tested on a small number of people from a population of interest to see side effects, appropriate dosing, and so on for that population. And Japan using this approach a lot. The medication that was tested safe and effective from global trials that are subsequently tested in Japanese patients. Here's one more listener question.

Federica Santoro 19:39

Michael asks, although the ultimate goal of pharmacogenomics is to reduce side effects, I imagine monitoring is still important. Is there any difference in how precision treatments are monitored for safety compared to traditional treatments? What are you saying?

SPEAKER_00 19:59

Well, there are drugs that include detailed information in product information on genetic factors. And you may find three tiers of information. One is a mandatory, one is a recommendation, strongly recommended or weakly recommended, and then just for information. And the follow-up may depend on the level of requirement or recommended screening or testing. For mandatory testing, you may need a lot of evidence and to really see the biomark is effective and leading to positive results. And for just for information, you may need to follow up whether the awareness has been increased. The different levels of recommendation is depending on the strength of association and the support of the usefulness of the genomic biomarkers and also the added value of the genetic testing compared with the usual clinical monitoring. It could be necessary to investigate whether a genomic biomarker guide use of a medicinal product has been effective or not, because there are special reasons genomic biomarker may not be effective. For example, if the recommendation is not feasible or not realistic, that you require a genomic testing that may take time for an urgent indication. And the genetic method may not be appropriate. If you do not find old variants, then you could not be sure that old patients with the virants are identified. And then the message needs to be very clear, to be understandable, and um how to make a decision. The impact on clinical decision making should be clear. And also it should be implemented. If you have a very good recommendation, but it's not implemented in clinical record system and the physician are not aware of this, then it's still not used.

Federica Santoro 22:14

So it sounds like there's still quite a few hurdles that need to be overcome before genetic profiling can become a standard practice in the clinic. In your opinion, what will it take to achieve true individualized drug therapy?

SPEAKER_00 22:31

Yeah, that's right. There are different kinds of hurdles. The first hurdle is you need good evidence. And to generate good evidence, you may need good clinical trials. And so far, one of the major limitations that has prevented the use of pharmacogenomic testing in clinical setting is the lack of prospective clinical trials for many drugs. To demonstrate the usefulness of pharmacogenomic biomarkers in assisting the drug selection and dosing of each individual, and also the extent to which genetic factors are contributing to drug response or toxicity that will not only depend on the gene effect itself, but there are other non-genetic factors, such as drug-drug interaction. And another limitation is the insufficient predictability of the pharmacogenomic biomarker test for recommending genotyping guided dosing. One example is for wolfarin. The genetic variants for V-Core and for SYP2C9 have been shown to be associated with wolfarin dosing requirements. However, the randomized clinical trial have not shown clearly the advantage of genetic screening compared with the routine monitoring. So you may need to show the added value here. And other hurdles, as already mentioned, you need regulatory labeling to require the recommendation, to require the screening, testing, or recommend testing. And then you need to implement and the awareness, as already mentioned.

Federica Santoro 24:21

So there's a lot that remains to be done. And obviously, integrating pharmacogenomics in clinical practice will be a lot easier for some countries than for others. And that's something that our listener Alexandra also asked about. She wonders if pharmacogenomics is even feasible in countries that lack the infrastructure for it. Many low-income countries will not have the funding, the resources, or the knowledgeable staff, she says, to carry out genetic screening and post-marketing surveillance in their communities. What would you say to that?

SPEAKER_00 25:02

This is a very relevant question. In addition to good evidence, regulatory labeling recommendation, the genomic biomarker testing has to be implemented. And the challenge in low-income countries with issues of resources, knowledgeable staff, etc., that are well acknowledged. And even in Europe, the situation varies a lot between countries. But the good news is that there is some evidence showing that hospitalization and emergency department visit can be reduced by genotyping elderly polypharmacy patients. And pre-prescription genotyping is cost-effective for certain ADRs. So there is a need to increase the awareness, especially for the decision maker, to make long-term plans, I think.

Federica Santoro 25:58

You have a long-standing interest in pharmacogenomics, obviously. And since 2020, you also chair the special interest group on pharmacogenomics at ISOP, the International Society of Pharmacovigilance. How is this group helping to advance the science of pharmacogenomics?

SPEAKER_00 26:20

Well, the pharmacogenomics members all have the special interest and they come from a different continent, different countries. The ISOP created this platform to provide an opportunity for ISOP members interested in pharmacogenomics to share and provide information on relative issues and development and also support pharmacovigilance relevant to medicinal products with pharmacogenomic association. So through meetings, training activities, etc. We have had an activity last year in the Patient Safety Day to spread information and increase the awareness, in particular the low-income countries.

Federica Santoro 27:09

And finally, what lies ahead? What developments would you like to see in the future of pharmacogenomics?

SPEAKER_00 27:17

I would like to see more education, increase awareness, and information on individuals' genetic status, the genotyping results. I would also like to see more research and better design in clinical trials and better labeling with more specific indications and usage guided by pharmacogenomic in subpopulations. And lastly, better implementations of the recommendation for genomic biomarker testing.

Federica Santoro 27:52

Thank you so much for taking the time to talk to me, Ying, and also for answering our listeners' questions. I'm sure they'll be delighted to hear your answers. I wish you all the best in your work. Thanks again. Thank you. That's all for now, but we'll be back soon with more conversations on medicine safety. If you'd like to know more about pharmacogenomics or ISOP's special interest group, check out the episode's show notes for useful links. If you like our podcast, subscribe to it in your favorite player so you won't miss an episode. And spread the word on social media so other listeners can find us. Apart from these in-depth conversations with experts, we host a series called Uppsala Reports Long Reads. A selection of audio stories from UMC's Pharmacovigilance magazine, so do check that out too. Uppsala Monitoring Center is on Facebook, LinkedIn, and Twitter, and we'd love to hear from you. You can send us comments or suggestions for the show, and don't miss the next opportunity to send in questions for the speakers. We'll be advertising that on social. For Drug Safety Matters, I'm Federica Santoro. I'd like to thank Chun Ying Yu for her time, Matthew Barwick for production support, our listeners Nicole, Alexandra, Nikita, and Michael for sending in questions, and of course you for tuning in. Till next time.