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Rare adverse drug reactions and genetics

This tutorial by Professor Yoon Loke explains how genetic variation can influence susceptibility to serious adverse drug reactions
Welcome to this session. We will look at serious rare adverse effects of drugs and whether the introduction of genetic testing can help us prevent some of these adverse reactions. To start with, we will look at the importance of adverse effects and consider the risk factors for these adverse effects. We will also discuss areas where genetic influence may affect the risk of these adverse effects. After that, we were going to discuss studies of clinical utility to determine whether genetic markers can help us prevent adverse reactions from occurring in individual patients. We should also consider the cost-effectiveness of implementing such genetic testing strategies in reducing the incidence of adverse reactions.
Why do adverse reactions occur in patients. Some of the adverse events are dose related. There’s a greater risk of harm as the dose of the drug is increased. Often, we can find a pharmacokinetic or a pharmacodynamic relationship between the drug and the occurrence of the adverse event. In many instances, the adverse event is related to time or duration of treatment. This may be how long the drug has been taken, or how often the drug has been used in that particular individual. For instance, some adverse events occur due to a high cumulative dose over a long time period. Or the adverse event may occur because of a high frequency of use of the particular drug.
Equally, there are susceptibility factors that affect individual patients. Those are the extremes of age, for instance, the very young or the very old may be more susceptible. Equally patients with physiological impairment such as those in renal or liver impairment are more likely to experience adverse effects. And finally, there may be genetic variations that lead to increased of adverse reactions in patients. So one of the main interests of prescribers is to minimise harm for the individual patient. What steps can be taken? Well, obviously careful selection of the drug for the patient would be a good first step.
If a patient has high risk of a particular adverse event then it would be helpful to avoid the drug or to adjust the dose, or duration, or treatment, so that this risk is reduced. Equally, we can put in careful monitoring to detect any problems and to adjust the treatment regimen accordingly. However, all of these steps are difficult to implement. If the serious adverse reaction happens to be an immediate hypersensitivity or serious allergy that occurs for the first or the very early doses. In such instances is it possible for us to identify some warning marker in these susceptible individuals ,so that we can avoid using the drug and avoid the patient from being harmed by such a reaction?
I believe that the role of genetic testing is best seen with serious or fatal out-of-the-blue adverse events. These are idiosyncratic reactions where there’s no clear relation to any measurable pharmacological mechanism and there’s no simple method of adjusting the dose, or identify patients who are at high risk of these adverse reactions. However, if genetic susceptibility could be measured then we could avoid harm and propose alternative treatments to the patients.
Now, what are the clinical settings where genetic testing might be justified? Well, first of all the drug has to be of proven value and there are no reasonable alternatives available for the patient. The adverse event is likely to be something that severe or life-threatening. Obviously, the patient’s condition should not be one that rapidly deteriorates while awaiting the results of a genetic test. Now, what makes the genetic testing worthwhile from a cost economic basis? Well, ideally the marker has to have a reasonably high prevalence in that patient group and the genetic test should have good predictive accuracy. Let’s look at an example of clinical utility with a drug known as carbamazepine. This is a drug that’s used for epilepsy.
It has been associated with dangerous or fatal skin reactions which typically occur within the first few months of treatment. The serious skin reactions are rare in European and North American populations, with the incidents are approximately 1 to 6 cases per 10,000 new users of carbamazepine. However, there’s a far higher incidence, up to ten times higher, in fact, in Chinese populations. And these severe skin reactions are significantly more likely if you carry a HLAB1502 allele. This allele has a higher prevalence in China, Taiwan, Thailand, Singapore, Malaysia, in up to 10% of the population in those countries. In contrast there’s a very low prevalence of less than 1% in non Asian countries.
Hence the US regulators have advised that we should screen patients with ancestry from the relevant countries and to avoid carbamazepine if HLAB1502 is detected. The cost utility economic model has been calculated in Thailand where it suggested that screening for this particular genetic variation offers value for money. Similarly, screening has also been implemented in certain centres in Taiwan. However, the low incidence of the allele and the lower likelihood of the adverse effect in European populations means that there’s little clinical utility in testing those particular groups. Now, there are other instances where testing for HLA type may help in preventing hypersensitivity reactions. Abacavir is a drug-using treatment of HIV.
There’s an incidence of about 8% of hypersensitivity reactions that occur within six weeks of starting this drug. It is strongly associated with HLAB5701 allele. Studies have shown that there’s a positive predictive value of about 50% - about half of those with the allele may develop an adverse reaction. The negative predictive value is much higher at about 100 percent. Those without the allele will not suffer a hypersensitivity reaction. There’s randomised trial data indicating that screening for this particular allele and decisions based on the data leads to a significant reduction in hypersensitivity reactions. So just to recap what we’ve been through in this
session: there are many causes of adverse drug reactions, and genetic susceptibility may have a major part in certain serious reactions. Identification of certain genetic markers may be helpful in predicting the risk of adverse reactions. And genetically guided treatment strategies have been trialed in certain groups of patients however, predictive value, ease of use, and cost-effectiveness must be thoroughly vetted before deciding the best strategy to use in preventing adverse drug reactions.
This tutorial by Professor Yoon Loke will explain how genetic variation can influence the susceptibility to serious adverse drug reactions.
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