Is there pre-emptive genotyping to avoid adverse drug effects (ADRs)?

Last Updated on November 20, 2022 by Joseph Gut – thasso

November 20, 2022 – The genetics of drug side-effects. Some 95% of people have a gene variant that affects their response to at least one drug. Treating physicians, clinical researchers, and affected patients know all to well the serious problems that unwanted adverse effects of medications (usually referred to as ADRs) can cause. Traditionally, pharmacogenomics is the study of how an individual’s genetic makeup influences their response to medications. Although the role of genetics in drug response has been studied for decades, broad pharmacogenomic testing has only more recently been integrated into prescribing decisions. Resources from groups such as the Clinical Pharmacogenetics Implementation Consortium (CPIC,with associated guidelines)and the Dutch Pharmacogenetics Working Group (DPWG) have allowed for more informed integration of pharmacogenomics into prescribing decisions, but different perspectives on the evidence needed for implementation of drug-gene pairs exist. Furthermore, pharmacogenomics implementation approaches vary regarding the timing of when the test should be ordered.

Some advocate that pharmacogenomic testing should be reactive and obtained only for certain medications prior to prescribing or after a patient has had an adverse reaction to the medication or is failing therapy. Others advocate for using a pre-emptive pharmacogenomic testing approach as a prevention and medication safety tool. A key assumption underlying the CPIC guidelines is that clinical high-throughput and pre-emptive (pre-prescription) genotyping will become more widespread, and that clinicians will be faced with having patients’ genotypes available even if they have not explicitly ordered a test with a specific drug in mind. One of the richest sources of possible pre-emptive associations of genes with drug actions and outcomes is PharmGKB, where pharmacogenetic evidence is assigned to pairs of  genes and related drugs according to Clinical Annotation Levels of Evidence and for PGx levels for FDA-approved drug labels assigning labels for the available informationof into “actionable pgx”, “genetic testing recommended”, or “genetic testing required”.

Overall, enormous genetic data sets may even help to elucidate an individual’s genetic background of a”metabolic profile” which may open the possibility to identify an individual’s risks for disease development and progression, not only to pharmacokinetic responses to drugs. Patients and families bring home the impact that gene-drug interactions can have, even with fatal consequences.

Such a case is the following. A female patient underwent surgery for breast cancer; the surgeon removed the tumor. In order to prevent micro-metastases, the patient should receive six courses of chemotherapy with fluorouracil (5-FU). During the second infusion of the drug, the patient collapsed, went to the intensive care unit and died. A blood sample taken later showed she had an allelic  variant of the DPYD gene that is known to be linked to severe adverse events in carriers thereof. In fact, The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur. Genetic variations within the DPYD gene can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency. Those with partial or complete DPD deficiency have a significantly increased risk of severe, even fatal, drug toxicities when treated with fluoropyrimidines. Had the treating physician or he clinic performed an pre-emptive genotyping of the patient, of whom one knew that she is going to receive a compound highly toxic for some, an unnecessary death could have been prevented.

In 2005, Dutch pharmacy experts created a list of the gene variants known to alter the way certain patients respond to certain drugs. Since then, they have made recommendations for over 100 gene-drug interactions identified (see above for the today’s DPWG group). These genes are not at the basis of rare genetic disorders. Variants of these genes are normal differences in the DNA code between different people; they’re what makes some people have blue eyes and others brown, for example. But they may be at the basis of severe differences in drug responses of individual patients. Usually, these variations are not yet widely taken into account in medicine, and most prescribers still think that effects on patients are very rare, mostly because they are based on genetics. Thus, a widespread feeling of practitioners still is that the problem is academic and that one will deal with it in the future.

The resource at PharmGKB’s annotations page will tell another story. PharmKGB constantly annotates drug labels and or product monographs containing pharmacogenetic (i.e., theragenomic) information approved by regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), Swiss Agency of Therapeutic Products (Swissmedic), the Pharmaceuticals and Medical Devices Agency, Japan (PMDA), and Health Canada (Santé Canada) (HCSC). These annotations provide a brief summary of the pharmacogenetic information in the label, an excerpt from the label and a downloadable PDF file of the label in question with the respective pharmacogenetic information highlighted. This set of date illustrates that there is ample evidence and knowledge in the open, and waiting to be used pre-emptive in order to avoid fatal drug events as the one described above.

Afterthought

At the time, such pharmacogenetic variants were used to understand why certain patients responded badly to treatment. It was considered as an afterthought, used only once something had already gone wrong. This should change, and the time is now. Genotyping of patients bevor they are going to be treated with a medication, of which one knows that they may cause severe problem in susceptible individuals should become the norm. This is already mandatory, according to a selection of drug labels which demand “testing required” as indicated.  However, with the arrival of whole genome sequencing, of which more and more individuals take advantage, it should become possible that each patients genetic outfit (for example integrated in her/his patient record) can be checked for any genetic variants of genes that might be involved in the behaviour of an indented medication treatment to be applied. Beforehand of the treatment (i.e., pre-emptive).

In practice in the clinic, according to experiences by the DPWG Working Group, it turned out that on one hand, the electronic data systems would be in place, that however, on the other hand, not too many patients had either their whole genome data or their punctual genotyping data (i.e., tested for given gene variants) uploaded into these systems. The system did not generate alerts concerning given patients because the genetic information was not available.

This contrasts with the fact that about 95% of people have a gene variant that is known to affects their response to at least one medication. This is often due to changes in the way that this medication is broken down by the body. If it is metabolised slowly, even a standard dose of the drug can build up to high levels in the body and cause serious side-effects. A living example would be genetic variants for CYP2D6, a liver enzyme that is involved in the metabolism of a quarter of all marketed drugs. The gene exist in >100 allelic variants in the population and phenotypically, individuals con be grouped into ultrarapid-, rapid-, normal-, intermediate- und poor-metabolisers of drug. Thus, some patients will need a substantially reduced dose, while rapid metabolisers will need a higher dose than normal. Patients receiving lower doses should not be concerned about being undertreated; the still have the same drug levels (in the body) compared to a normal metaboliser who receives the normal 100% of the dose. In some cases, however, prescribers may recommend to switch to a different medication that is metabolised differently.

Ubiquitous (The Future)

The future should be that all individuals have their personal genome analyse, and these data are integrated into their individual patient records. The vision is that people would be tested for a panel of genetic variants or the whole genome, the results of which would then be linked to the individual’s health record. Upon questioning the according patient data systems, this would make the genetic predisposition for drug related adverse effects pre-emptively visible and would allow for an informative risk assessment by the physician on how and with which medication to proceed in a given patient and/or disease. In fact, the approach would allow for both, targeted therapies and truly personalised medicine in that  not all drugs and treatments are suitable for everybody.

In conclusion, the answer to the questions “Is there pre-emptive genotyping to avoid adverse drug effects (ADRs)” may be yes technically and scientifically, clinically yes in some cases, but at large not yet there and fully implemented.

See here a sequence on this important theme by Professor Pirmohamed, a real pioneer on ADR’s:

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