From Genotype to Prescription: How Germline Pharmacogenetics Is Reshaping Drug Safety

17 February, 2026

Genome Lens

Genetics severely impacts on the response to some drugs and adverse drug reactions (ADRs) remain a major and largely preventable burden for healthcare systems. In Europe, ADRs account for approximately 5% of hospital admissions, while in the United States they contribute to over one million emergency department visits annually. Germline pharmacogenetic (PGx) testing are actually in the spotlight representing one of the most clinically mature precision medicine tools to reduce this burden by improving drug selection and dosing.
To help clinicians on how to interpret and act upon their patients’ pharmacogenetic results several guidelines have been provided. Specifically, two U.S. and one European-based resources are crucial here, CPIC, the Pharmacogenomics Knowledge Base (PharmGKB) and the Dutch Pharmacogenetics Working Group (DPWG). As of July 2025, PharmGKB has transitioned to ClinPGx, a unified platform that integrates PharmGKB, CPIC, and other resources.

Clinical relevance in oncology: established and emerging markers

The most studies on pharmacogenetic associations have been implemented in cancer underlining the role of Cytochrome P450 (CYP) variants in drug response. For example, in breast cancer both CYP2D6 and CYP2C19 polymorphisms reduced the efficacy of tamoxifen and cyclophosphamide, respectively, impairing therapeutic efficacy. In addition, CYP3A4 polymorphisms affect the activity of TKI (imatinib , gefitinib) in GIST, lung cancer and sarcoma.

Genetic variations in the DPYD gene can result in partial or complete enzyme deficiency, which significantly affects the metabolism of 5-FU and capecitabine. This can lead to an increased risk of severe, and sometimes fatal, toxicities in patients. For this reason, ESMO, CPIC and other national guidelines recommend testing of DPYD variant prior to treatment with 5FU or capecitabine. As well, the UGT1A1 polymorphisms affect both the irinotecan efficacy and toxicity, a drug commonly used to treat metastatic solid cancers.

Variability in TPMT and NUDT15 enzyme activities, driven by genetic polymorphisms, can significantly influence both the efficacy and toxicity of thiopurine therapy.

Clinical relevance beyond oncology: established and emerging markers

PGx testing remains inconsistently implemented outside oncology, even though many high-impact gene–drug interactions involve commonly prescribed therapies used in routine clinical practice. Outside oncology, the value of PGx testing is driven by chronic drug exposure and polypharmacy. In cardiology, variants in CYP2C19, CYP2C9, VKORC1, and SLCO1B1 influence response and toxicity to antiplatelets, anticoagulants, and statins. In psychiatry, polymorphisms in CYP2D6 and CYP2C19 contribute to variability in antidepressant and antipsychotic efficacy and tolerability. In pain management, altered CYP2D6 activity affects opioid bioactivation, increasing the risk of inefficacy or adverse effects. Beyond genes already embedded in guidelines, additional markers with strong supporting evidence remain underutilized. As examples, SLCO1B1 variants are strongly associated with statin-induced myopathy, yet testing is not univocally recommended despite widespread statin use. As well, variants in ABCG2 influence the pharmacokinetics of drugs such as rosuvastatin and allopurinol, with reduced transporter activity linked to increased exposure and toxicity are not routinely tested. Similarly, UGT1A1, currently tested mainly to reduce irinotecan toxicity, may have broader relevance for other drugs cleared via glucuronidation pathways.

Socio-economic impact and implementation evidence

A growing body of quantitative evidence supports the clinical and economic value of PGx testing, particularly when implemented pre-emptively. In the United States, pre-emptive pharmacogenetic implementation programs such as those within the IGNITE network have shown that over 90% of individuals carry at least one actionable pharmacogenetic variant, supporting the potential for broad clinical impact. Economic evaluations further indicate that pre-emptive PGx testing approaches cost-saving thresholds in modeled scenarios where patients are exposed to multiple actionable drugs over time—an increasingly common situation in chronic disease management. In Europe, health economic modeling from the Netherlands estimated that testing a core set of pharmaco-genes (CYP2C19, DPYD, TPMT, UGT1A1) could prevent over 1,000 severe ADRs annually, with cost per quality-adjusted life year (QALY) well below accepted thresholds. These findings support PGx testing as a preventive intervention with measurable system-level value.

Regulatory landscape, reimbursement, and remaining gaps

Regulatory agencies such as the FDA and EMA formally recognize the relevance of pharmacogenetics, yet translation into routine care remains uneven. Clear alignment exists for a limited number of biomarkers, including mandatory HLA-B57:01* testing for abacavir and recommended DPYD testing for fluoropyrimidines in Europe. However, many drugs with strong pharmacogenetic evidence provide only partial or non-actionable guidance in their labels.

Reimbursement further shapes adoption. In the United States, coverage is largely payer- and indication-specific, while in Europe reimbursement policies remain fragmented, often limited to single-gene tests and dependent on regional funding. This combination of regulatory ambiguity and heterogeneous reimbursement continues to slow large-scale implementation.

In addition, trial activity is concentrated on a limited set of pharmacological agents and genes with a lot of drug/gene integrations remaining underexplored.

Conclusion

For clinicians, molecular biologists, and diagnostic stakeholders, the challenge is no longer scientific validation but implementation. Aligning clinical evidence, regulatory communication, and reimbursement frameworks is essential to move germline pharmacogenetic testing from selective use to routine preemptive care.

Through the genome lens, pharmacogenetics emerges as a cornerstone of precision medicine—capable of improving drug safety, optimizing therapeutic outcomes, and supporting more sustainable healthcare systems.

References

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