Dynamic phenotype monitoring to prevent genotype–phenotype discrepancies in pharmacogenetic-guided drug therapy

Pharmacogenomic biomarkers in oncology: evidence, clinical utility, and barriers to implementation.

Interpatient variability in chemotherapy response and toxicity remains a major challenge in oncology. Pharmacogenomics (PGx) is an approach to address this challenge by combining somatic alterations that affect tumour sensitivity with germline variants that affect drug metabolism, transport and toxicity. This review provides a critical evaluation of clinically validated PGx biomarkers for chemotherapeutics and targeted therapy with a focus on translational relevance and strength of evidence. High-impact germline markers such as DPYD, TPMT, NUDT15 and UGT1A1 are highlighted as key determinants of genotype-guided dosing for improving safety without compromising efficacy. Somatic biomarkers such as EGFR, RAS, BRAF, and HER2 remain central to treatment selection, while resistance underscores the need for ongoing molecular assessment. A tiered implementation framework, barriers to progress, and future directions involving polygenic models, multi-omics, and artificial intelligence (AI) are discussed to advance safe, effective, and personalized chemotherapy.

Pharmacogenomics of Adverse Drug Reactions: Integrating Genetic Biomarkers into Precision Pharmacotherapy

Adverse drug reactions (ADRs) remain a major global healthcare challenge, accounting for significant morbidity, mortality, treatment failure, and increased healthcare expenditure. Although clinical factors such as age, comorbidities, organ function, and polypharmacy contribute to ADR susceptibility, they inadequately explain the marked interindividual variability in drug response. Pharmacogenomics has emerged as a transformative approach to precision medicine by identifying inherited genetic variants that influence drug metabolism, transport, efficacy, and toxicity. This review critically examines the role of pharmacogenomic testing in predicting, preventing, and managing ADRs, with emphasis on clinically actionable pharmacogenes including CYP2D6, CYP2C19, TPMT, NUDT15, HLA-B15:02, HLA-B57:01, and HLA-B 58:01. Evidence from international pharmacogenomic guidelines demonstrates that genotype-guided prescribing significantly reduces severe hypersensitivity reactions, drug toxicity, and treatment failure while improving therapeutic efficacy and patient safety. The review further discusses current clinical applications, implementation challenges, ethical considerations, and emerging advances in genomic technologies, artificial intelligence, and clinical decision-support systems. The integration of pharmacogenomics into routine healthcare has the potential to optimize individualized drug therapy, minimize preventable ADRs, and accelerate the transition toward precision medicine, ultimately improving clinical outcomes and healthcare quality.

Pharmacogenetics and Pharmacogenomics as Enabling Technologies for Precision Drug Development and Personalized Therapy.

Clinical Implications of UGT1A1 Polymorphisms in Anticancer Therapy: An Updated Review

Pharmacogenetics has transformed oncology by enabling personalized, effective and safer use of anticancer therapies. Among clinically relevant pharmacogenetic biomarkers, polymorphisms in the UGT1A1 gene influence the metabolism of irinotecan and other SN-38-based agents, increasing the risk of treatment-related toxicities. Beyond SN-38-based therapies, UGT1A1 contributes to the metabolism of endogenous compounds and several drugs, and its activity may be affected by concomitant inhibitors or inducers, highlighting its broader clinical relevance. Although substantial evidence supports the association between UGT1A1 genotype and drug safety, implementation of genotype-guided treatment remains inconsistent. This narrative review summarizes the biological basis and clinical relevance of UGT1A1 polymorphisms in patients receiving SN-38-based therapies. Original studies, systematic reviews, meta-analyses, and international and regional pharmacogenetic guidelines were evaluated regarding genotype-guided dosing, clinical outcomes, implementation strategies, and barriers to routine testing. Reduced-function UGT1A1 variants are associated with increased risk of irinotecan-induced neutropenia and diarrhea, particularly at higher doses. However, recommendations from scientific societies differ regarding testing indications, dose adjustment strategies, and patient selection. Uncertainties remain concerning the clinical implications of UGT1A1 variability for newer antibody–drug conjugates carrying an SN-38 payload. Practical barriers, including inconsistent guideline recommendations, limited access to testing, reimbursement issues, and heterogeneous clinical workflows, continue to restrict implementation. UGT1A1 genotyping represents a valuable tool for improving the safety of selected anticancer therapies, yet its incorporation into clinical practice remains incomplete. As precision oncology evolves, pharmacogenetic testing may optimize treatment selection, reduce toxicity, and improve outcomes. Further harmonization of international recommendations, high-quality prospective studies, and wider access to pharmacogenetic testing are needed to support routine implementation.

Pharmacogenomics and Precision Pharmacotherapy in Heart Failure: A Narrative Review

Heart failure is a life-threatening condition affecting approximately 1% of the global population, with its prevalence continuing to rise. Genetic factors, including pathogenic variants in sarcomere, cytoskeletal, and ion channel genes, contribute to disease progression, often following Mendelian inheritance patterns. However, most interindividual variability in disease course and therapeutic response arises from polygenic, non Mendelian patterns, particularly single nucleotide polymorphisms (SNPs). SNPs can modestly influence gene expression, protein function, and downstream signaling pathways, thereby affecting the pharmacokinetics and pharmacodynamics of cardiovascular drugs. Variants in genes such as CYP2D6, ACE, AGT, CYP11B2, ADRB1/2, SLC5A2, and UGT2B4 have been associated with differential responses to β-blockers, SGLT2-inhibitors, and ACE inhibitors. The clinical application of genomic approaches remains limited due to small study sizes, interpatient variability, and the lack of standardized biomarkers. Nevertheless, integrating genetic, epigenetic, and phenotypic data offers a promising strategy to guide more effective and individualized heart failure pharmacotherapy.

Metabolomics and Precision Medicine in Resistant Hypertension: Pathophysiological Insights, Biomarker Discovery, and Translational Strategies

Resistant hypertension (RH), defined as uncontrolled blood pressure despite the use of at least three optimally dosed antihypertensive agents, including a diuretic, remains a major clinical challenge associated with elevated cardiovascular risk. Metabolomics offers a dynamic approach to characterize biochemical perturbations related to amino acid metabolism, lipid remodeling, mitochondrial dysfunction, oxidative stress, renal impairment, and gut microbiota–derived metabolites. However, current evidence remains limited by small sample sizes, cross‐sectional designs, heterogeneous definitions of RH, inadequate exclusion of pseudoresistance, medication confounding, and limited external validation. This structured narrative review synthesizes RH‐specific metabolomic evidence and distinguishes it from findings extrapolated from broader hypertension populations. We further discuss methodological challenges, replication gaps, pharmacometabolomic confounding, and validation standards required for clinical implementation. Integrating metabolomics with clinical phenotyping, genomics, proteomics, and microbiome profiling may eventually support RH phenotyping, treatment–response prediction, and biomarker‐guided precision medicine, but large longitudinal cohorts with confirmed true RH are needed before clinical translation.