Across centuries, the intricacies of individual responses to both food and medicine have intrigued scholars and practitioners alike. From the ancient observations of Pythagoras, who noted the haemolytic reactions to fava beans, to modern genomic insights, such variations continue to shape medical understanding. Today, we recognize glucose-6-phosphate dehydrogenase deficiency, stemming from mutations in the G6PD gene, as a global concern impacting millions.

In the lexicon of health care, the terms pharmacogenomics and pharmacogenetics are frequently used interchangeably, representing the study of how genetic factors influence drug responses. Yet, a more expansive view of pharmacogenomics emerges, one that transcends individual reactions to drugs. Embracing cutting-edge genomic technologies, this field seeks not only to optimize drug efficacy and safety, but also to revolutionize drug discovery and personalized treatment strategies. As such, pharmacogenomics stands at the forefront of a new era in precision medicine, promising tailored solutions to healthcare challenges on a global scale.

While pharmacogenomics has traditionally been the domain of academic research, policymakers are now showing a burgeoning interest in its potential to enhance patient outcomes, paving the way for its integration into clinical practice. Furthermore, mounting evidence from the pharmaceutical industry underscores the value of genomically defined targets in boosting success rates in drug development, fueling additional interest and research in this field.

A Precise Pairing

Drug-gene pairs emerge as crucial players in determining how individuals respond to treatment across diverse therapeutic landscapes from immunosuppressants to antiplatelet agents. The term “drug-gene pairs” denotes the specific interactions between a patient’s genetic makeup and the medications they receive. However, they’re far from uniform. Gene variant frequencies can fluctuate significantly, ranging from a modest 4% to a staggering 74%, directly influencing the severity of potential drug toxicity.

For the implications for patients grappling with compromised medication metabolism, the stakes are high with adverse effects ranging from discomfort to life-threatening outcomes, including hospitalization or death. Yet, amidst the challenges lies a glimmer of hope. Through testing for genomic variants associated with medication tolerance, a new frontier emerges in the form of precision medicine.

The DPD Dilemma

To unravel the narrative of pharmacogenetics, let’s delve into the story of dihydropyrimidine dehydrogenase (DPD) — the biochemical protagonist summoned to play a crucial role in the theatrical production of a cancer patient’s chemotherapeutic journey. Like any compelling drama, DPD may reveal itself as either a hero or a potential villain in this intricate narrative.

Nestled within the liver lie the DPD enzymes, orchestrators of fluoropyrimidine (FP) — the most widely used anticancer drugs worldwide — metabolism that wield a profound influence on FP processing. Through their expression of drug-metabolizing enzymes, the liver intricately modulates the capacity to metabolize medications upon exposure. Remarkably, the inter-patient variability in DPD extends far beyond a single drug, spanning across the diverse drug classes of FPs commonly used in several cancer types, including gastrointestinal, head and neck, and breast cancers.

The use of FP chemotherapy agents — namely 5-fluorouracil (5-FU) and the pro-drugs capecitabine and tegafur — presents a notable conundrum in clinical practice, marked by the emergence of severe and potentially life-threatening toxicities, including low white blood cell counts (neutropenia), diarrhea, inflamed mouth and throat (mucositis), and rashes or sores on the hands and feet (hand-foot syndrome). How do genes implicate themselves in such unpleasant manifestations?

Surprisingly, less than 5% of the main FP (FU) transforms into its potent active form with a whopping 80% taking an alternative route, courtesy of the DPD enzyme. This enzyme, however, isn’t without its quirks; variations in its activity from one patient to another are partly due to genetic differences in the gene encoding the enzyme DPYD. Enter the DPYD carriers, a group comprising roughly 7% of patients, who bear one of four confirmed faulty (pathogenic) germline DPYD variants. On the flip side, about 93% of patients are the wild-type (WT) players, lacking these troublesome DPYD variants.

Why does this genetic lineup matter? DPYD plays the role of a prototypical pharmacokinetic gatekeeper, where DPYD carriers experience a reduction in DPD activity. The consequence? Higher systemic exposure to FU and an increased risk of toxicities associated with FPs.

Consequently, upfront genotyping has emerged as an essential prerequisite for fluoropyrimidine (FP)-based chemotherapy treatments. This imperative has been underscored by a plethora of guidelines endorsed globally, with notable backing from the European Medicine Agency (EMA). Swiftly translating EMA’s directive into national consensus guidelines, many European countries have adopted the routine use of molecular diagnostics kits for pharmacogenomic testing of FP-based therapy, marking a significant stride in the integration of pharmacogenomics into clinical practice.

The UK, in particular, has witnessed a monumental shift with the introduction of DPYD testing, catapulting the National Health Service (NHS) into the forefront of pharmacogenomics. Representing the largest pharmacogenomics testing initiative in NHS history, the nature of DPYD testing is characterized by urgency and high volume, demanding both speed and sensitivity. Real-time polymerase chain reaction (RT-PCR) has emerged as the swiftest and most cost-effective method for DPYD testing, setting a precedent for the streamlined expansion of pharmacogenomic screening across diverse drug classes in various medical specialties.

The Promise of Pharmacogenomics

This specific application of pre-emptive testing marks a wider trend of using tumour biomarker tests to stratify patients according to their tumour prognosis and prediction of response to cancer treatment, among other possible biomarker uses. And so, pharmacogenomics unveils a profoundly personalized approach, where genetic variants that clinically modify the tolerability and desired effect of specific medications potentially transforms patient care by enhancing treatment outcomes and reducing adverse effects.

By delving into the genetic variations that influence drug metabolism and efficacy, pharmacogenomics offer healthcare providers invaluable insights into tailoring treatment regimens to suit each patient’s unique genetic profile. From antidepressants to cholesterol-lowering agents, the applications of pharmacogenomics span a multitude of therapeutic classes.

With advancements in technology enabling more accessible and cost-effective genetic testing, the integration of pharmacogenomics into clinical practice holds promise for a future where treatments are not only personalized but also optimised for efficacy and safety. As stakeholders across the healthcare ecosystem embrace this innovative approach, the dawn of a new era in medicine beckons on the horizon — one characterised by tailored interventions and improved patient outcomes.

Despite the promising potential of pharmacogenomics, its journey into mainstream clinical practice has been frustratingly sluggish. Yet, this delay is not for lack of excitement surrounding its possibilities. The vast troves of genomic data now available are reshaping the landscape of drug discovery and development. With insights gleaned from genetic analyses, researchers are not only improving success rates but also enhancing safety evaluations in the early stages of drug development. This deeper understanding enables the identification of potential risks that may elude traditional preclinical toxicology studies.

However, pharmacogenomics is just one piece of the puzzle in the broader quest for personalized medicine. While genetic variations undoubtedly influence medication response, not every gene-drug combination merits a shift in clinical prescribing practices. It is essential to recognize that medication toxicity isn’t solely determined by gene variants. To truly individualize treatment approaches, we must incorporate a multitude of factors, including clinical data such as age, sex, and body weight, alongside genetic information and other Omic biomarkers. This multidimensional approach is essential for developing comprehensive algorithms that guide treatment decisions.

Amidst these advancements lie challenges. From regulatory hurdles to ethical considerations, the path forward is not without obstacles. However, these challenges are not insurmountable. Through collaborative research efforts and the innovative application of digital therapeutics, we have the opportunity to overcome these barriers and pave the way for a future where healthcare is truly tailored to the individual.