Pharmacogenomics: advancing toward personalized medicine

Individual variability in response to different foods and medications was observed as far back as ancient times. One such example comes from Pythagoras, who noted that consumption of fava beans caused hemolytic anemia in some individuals but not in others. While the cause was unknown at the time, we now understand that this reaction results from a genetic mutation leading to a deficiency of the enzyme glucose-6-phosphate dehydrogenase. Although it may seem intuitive today to associate genetics with disease, it took a long time for this connection to be fully established and scientifically validated.

Pharmacogenomics – the foundation of personalised therapy

Pharmacogenomics is a branch of pharmacology that studies how an individual’s genetic factors influence their response to medications. It aims to answer questions such as why some people require higher or lower doses to achieve a therapeutic effect, and why certain individuals fail to respond to treatment altogether. This discipline is applied in predicting optimal drug dosages, improving drug efficacy, preventing side effects through genotyping for risk alleles, anticipating the activation of prodrugs into active metabolites, and facilitating drug discovery and development. By selecting both medications and their dosages based on an individual’s genetic profile, pharmacogenomics paves the way for personalized medicine and the tailoring of therapy to each patient.

How genes shape our response to medications

In addition to clinical factors that influence drug action—such as lifestyle, age, body weight, sex, and kidney or liver function—there are also genetic variations that affect how individuals respond to medications. These genes, known as pharmacogenes, play a role in determining both the pharmacokinetics and pharmacodynamics of a drug. It is believed that the majority of people carry at least one genetic variant that leads to an abnormal response to specific medications. Examples of pharmacogenetic variations and their impact on treatment outcomes include the CYP2C19 enzyme polymorphism (most commonly due to point mutations), which results in reduced enzymatic activation of clopidogrel. This can lead to an increased risk of thrombosis in high-risk patients. Additionally, polymorphisms in the CYP2C9 and VKORC1 genes can enhance the activation of warfarin, increasing the risk of bleeding in carriers of these mutations.

Applications of pharmacogenomics

The established role of pharmacogenomic variations in determining drug efficacy and safety has prompted the development of clinical guidelines for the implementation of pharmacogenomics by international scientific consortia. The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have developed validated guidelines for several gene–drug interactions. Today, pharmacogenomic testing is increasingly integrated into clinical practice prior to initiating treatment with certain medications, such as the aforementioned clopidogrel and warfarin, as well as carbamazepine and others. Testing is typically performed using a blood sample, saliva, or buccal swab, and the identification of genetic polymorphisms is carried out using molecular diagnostic methods, with PCR being the most commonly employed technique. 

Between potential and challenges

Pharmacogenomics is steadily paving the way toward personalized medicine and safer pharmacotherapy. Although still an emerging field, its impact is already evident in certain areas of clinical practice. Numerous recent advances in pharmacology and genomics have enabled physicians to tailor treatments more precisely, ensuring the right drug for the right patient. Naturally, progress in this area of science faces several challenges, but with ongoing developments in research and technology, many of these obstacles are likely to be overcome in the near future.

Translated by: Josip Kokanović