Introduction

Medication Safety Week serves as a crucial reminder of the importance of ensuring that medications are used safely and effectively. While traditional medication practices rely on general guidelines, the field of pharmacogenomics (PGx) is changing the way drugs are prescribed and administered and moving us towards a precision medicine approach to healthcare. By leveraging genetic information, PGx allows for more precise, personalized treatments that minimize adverse drug reactions (ADRs), manage side-effects and optimize therapeutic outcomes.

In this blog post to mark Medication Safety Week, we explore the significance of PGx in medication safety, its applications in various medical fields, real-world success stories and what the future holds for this game-changing test for enhanced therapeutic interventions.

Understanding PGx

PGx is the study of how an individual's genetic makeup influences their response to medications, and we have described this technology in many of our previous blog posts. Traditional prescribing methods operate on a "one-size-fits-all" approach, often leading to variability in drug efficacy and safety. PGx helps bridge this gap by identifying genetic variants that impact drug absorption, metabolism, efficacy, and, importantly for Medication Safety Week, its potential toxicity.

Fig 1 Key concepts in PGx. Pharmacogenes encode proteins that affect drug absorption, metabolism, and excretion, or are the direct targets for drugs- some key genes are highlighted in this graphic along with the tissues where they are most highly expressed. Profiling the genes involved in these processes is used to identify the metabolism status of an individual for that drug. By integrating PGx into clinical practice, healthcare providers can tailor medication choices and doses to each patient’s genetic profile, thereby enhancing both the safety and effectiveness of the medication.

How PGx Enhances Medication Safety

There are a number of different ways that PGx testing is being used to improve drug safety, but one key area is in the identification of an individual’s risk of Adverse Drug Reactions (ADRs). Even though most of us never think about them, ADRs are a leading cause of hospitalizations and medication-related deaths, and in the US 3-8% of hospital admissions are related to ADRs (Einarson 1993; Moore et. al. 1998). PGx is being used to predict a patient’s risk of ADR by identifying pharmacogene variants that significantly impact how this patient metabolizes certain drugs, resulting in potentially toxic levels of the drug; one of the most commonly cited examples describes variants of the CYP2C19 gene that can result in a reduced response to the blood thinner clopidogrel. CYP2C19 intermediate and poor metabolizers who receive clopidogrel do not process the drug to its active form and therefore experience reduced platelet inhibition and increased risk for major cardiovascular and cerebrovascular (Dean and Kane, 2012). Another commonly referred to example involves individuals with variants in TPMT resulting in reduced enzyme activity who may experience severe toxicity or bone marrow suppression to thiopurine medications such as azathioprine or 6-mercaptopurine (Wei et. al. 2012; Wilke et. al. 2009).

There are caveats to the impact of pharmacogene variants based on if the medication is administered in the active form of the drug, or as a so-called prodrug that the body converts into the pharmacologically active drug. PGx-driven metabolic profiles range from ultra-poor metabolizers (no or very low enzyme activity) through to intermediate and normal metabolizers (low to normal enzyme activity) up to ultrarapid metabolizers (very high enzyme activities). The impact of the patient’s metabolic profile on the response to the medication, is different for drugs versus prodrugs, as summarized below in Fig. 2.

As more pharmacogenes are identified and clinical data supporting their impact on the safety of various drugs is published, PGx testing is proving to be a simple and cost- effective tool for enhanced patient safety. ADRs are a significant public health issue, that for the most part is preventable (Weiss et. al. 2024), and PGx testing is a key part to that prevention.

ADRs are classified in two distinct forms, Type A that represent an extension of the drug’s therapeutic effect and are therefore dose-related; and Type B that are more unpredictable and often idiopathic. However, PGx testing is useful in the prediction of risk for both Type A and B ADRs with the growing understanding of how pharmacogenes impact drug metabolism. Since all drugs have the potential for ADRs, the clinician needs to balance the risk and benefit when a new medication is prescribed, and PGx guidelines are now a central component in this determination.

Fig. 2. PGx testing is used to generate a metabolic profile for an individual based on the variants of the pharmacogenes involved in the processing of the drug. The effect of this metabolic profile is different for medications where in administered drug is in the active form versus prodrugs, which are metabolized to the active therapeutic molecule. It is important to understand these differences to flag individuals who are at risk of ADRs from certain medications based on their metabolic profiles.

Table 1 summarizes a list of common medications with risks for severe liver damage, along with the key pharmacogene variants associated with this risk; this is by far from a complete list, and to date there are more than 217 medications with PGx guidelines associated with their use https://www.personalizedmedicinecoalition.org/research/pgx-drug-gene-associations/

Table 2. CPMC-WD Therapeutic warfarin dosing (mg/week) based on CYP2C9, CYP4F2 and VKORC1 variants -algorithm is used to determined optimal dose (www.warfarindosing.org).  (Shahabi et. al. 2016)

Warfarin dosing is being optimized using a variety of tools that enhance precision and minimize risks of potentially lethal adverse effects. Clinical decision support systems (CDSS) integrate patient data such as INR (International Normalized Ratio) values and PGx profiles for CYP2C9, CYP4R2 and VKORC1 variants (Table 2) to make clinically driven dosing adjustments for enhanced patient safety.  The incorporation of Machine learning algorithms that analyze a patient history and risk factors are also helping to refine dosing recommendations, and as such promoting safer long-term use of this critical drug.

Final Thoughts

Medication Safety Awareness Week emphasizes the importance of safe medication practices to prevent errors, adverse drug reactions, and misuse.  It is a multifaceted endeavor requiring oversight at many levels starting with clinicians and pharmacists who should work together to verify prescriptions, and provide clear communication about medication purposes, side effects, and safe storage that are all crucial for patient adherence and safety. Patients should be educated to follow prescribed dosages, schedules, and instructions to ensure effectiveness and avoid harmful effects; and as the patient’s therapy continues, healthcare providers should regularly review patient medications to prevent harmful drug interactions and duplications and incorporate PGx to strengthen medication management and reduce polypharmacy and the dangers it brings.

This week serves as a reminder for healthcare professionals and the public to take simple proactive steps and incorporate innovative tools such as PGx testing to help ensure medication safety and better health outcomes for all.

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