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Pharmacogenetics evidence levels

Pharmacogenetics evidence levels

17/07/2021
Posted by:

Dr.M.Raszek


How the impact of pharmacogenetics is rated

Pharmacogenetics/pharmacogenomics is the study of how our genes impact the medications we take. Each one of us is programmed by having a variety of different mutations in our genes that influence how medications are processed by our body, and this information can be collected and then examined to help determine how medications should be dosed to best match how we metabolize (break down within our body) the medications we use, or even help avoid taking medication altogether because it could be toxic to us. For an additional background review on pharmacogenetics, check out Merogenomics past blog post.

Considering how many drugs are being prescribed, one would think that pharmacogenetic testing would be in great use right now. However, clinical implementation has been lagging behind. That is despite the fact that this is very well researched and the field boasts the presence of a great database that compiles levels of clinical evidence. While we previously touched on this topic, we wanted to briefly revisit it here in this post. Pharmacogenetic’s clinical levels of evidence range from the highest levels of evidence at 1A (highest level of medical literature support), followed by 1B (defining a gradient of accumulated evidence) moving to moderate levels of evidence, assigned scores of either 2A or 2B, then going down the ladder to lower level of evidence, referred to as level 3 and finally level 4 describing drugs for which only preliminary evidence is available.

Every medication for which any studies in relation to personal genetics have been done is assigned a specific level, ranging from 1A to 4. Obviously the higher the evidence level, the greater the security of being able to act on personal pharmacogenetic information for a given medication for any patient that has undertaken such DNA test.

Pharmacogenetics test levels of evidence

The pharmacogenetic test promoted by Merogenomics is one of the best we are aware of, and follows these criteria for levels of evidence.

Obviously, doctors will want to work with drugs that have the highest level of evidence. But let’s mention an interesting drug to show you how even a lower level of accumulated evidence could be of value when we are dealing with an important issue.

 

Imatinib pharmacogenetics – an example of low level evidence

This example is an important cancer drug called imatinib which also goes by the name of Gleevec. The pharmacogenetic DNA test that Merogenomics promotes reports on its metabolism by six genes (CYP 3A4/5, 1A2, 2D6, 2C9, 2C19), together combining to give level 2C evidence only. These genes code for molecular “robots” that break down chemicals such as these drugs. Molecular robots that are involved in alteration of other biomolecules are called enzymes. In this case these are metabolizing enzymes that break something down into smaller pieces (in this case the prescribed cancer drug). Of these six genes, CYP3A4 is the major enzyme and as per the FDA imatinib drug label, there is data to show the degree to which the imatinib drug remains intact (is not broken down) which can be dependent on anything that either induces or inhibits the enzymatic activity of the CYP3A4 gene. Thus, you can appreciate how the ability of CYP3A4 enzyme to work efficiently should also influence how much of the imatinib drug is prescribed to deliver its intended function.

However, when it comes to the two most definitive databases on clinical validation of a drug being influenced by personal genetics, imatinib does not fare very well: in the Clinical Pharmacogenetics Implementation Consortium (CPIC) database, which sorts available medical literature evidence to develop guidance for pharmacogenetic clinical use, imatinib does not have such guidance. When it comes to the other major database, PharmGKB, which sorts and organizes CPIC and additional available results into the above mentioned pharmacogenetic levels of supporting evidence, imatinib only has level 3 supporting evidence.

CPIC database

PharmGKB database

Thus since there are currently no guidelines for the use of imatinib in pharmacogenetic testing, it is difficult to have an actionable recommendation based solely off of the genetic results in an individual. The lower PharmGKB evidence would also play into this decision. This information may still be helpful in giving us insight into this medication's metabolism, but the pharmacogenetic DNA testing results for this drug should not be used solely to base a dosing recommendation. Clinicians should take into account all of the relevant patient factors such as condition history, med history, concurrent meds, organ function, etc., as well. That actually goes for all medications in relation to pharmacogenetic testing evidence but would be especially important for drugs with a lower evidence of support. But due to the importance of this medication, and despite the lower supporting evidence, it is still included in pharmacogenetic reports.

 

Clopidogrel pharmacogenetics – example of highest level evidence

This can be contrasted with a drug such as clopidogrel (Plavix), an antiplatelet medication used to reduce the risk of heart disease and stroke, a substrate of the CYP2C19 gene with the highest level of established evidence at level 1A. Clopidogrel is a prodrug, meaning it must be converted first to the active form via CYP2C19 enzyme to produce a metabolite that will then finally irreversibly bind platelets in order to prevent clotting. This is in contrast to active drugs which execute their function directly. Therefore, patients with a genetic mutations in the CYP2C19 gene information (such information is referred to as patient genotype) indicating they are a poor metabolizer, in a case of a prodrug like clopidogrel would actually not be converting the drug to active form and therefore the patient would still be at risk for clotting and a heart attack despite being medicated. In such cases, poor metabolizers of clopidogrel should consider switching to a different medication.

The take home message is that pharmacogenetic testing can be a very important tool in helping physicians determine how to prescribe medications based on personalized genetic information with the obvious hope of higher chances of success of medical treatment, including, as discussed above, potentially avoiding fatal consequences. When assessing pharmacogenetic reports, the level of established evidence can be important in guiding the management decisions, especially for the lower-level evidence medications. The same gene can have different levels of established evidence for different medications. For medications with the established highest levels of evidence, dosing clinical guidelines can be available for a doctor as well. Finally, it is important to note which medications are active drugs versus prodrugs, as their dosing impact will be reverse in terms of the risk of producing adverse events in case the patient is not an expected normal metabolizer.

 

This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

 

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