A review of pharmacogenomics in the individualization of pharmacological treatment: present and future

Abstract

Pharmacogenomics has become a central component of personalized and precision medicine, enabling the optimization of pharmacological treatments through the integration of genetic, clinical, and environmental information. Interindividual variability in drug response remains a major clinical challenge, contributing to therapeutic failure, adverse drug reactions (ADRs), and substantial healthcare costs. Although common polymorphisms account for part of this variability, a considerable proportion remains unexplained and is increasingly attributed to rare genetic variants, ethnogeographic differences in allele distribution, environmental factors, and phenomena such as phenoconversion. Advances in next generation sequencing (NGS) have revealed that most pharmacogenes harbor a high burden of rare variants, many with potential functional impact and marked population specific patterns, underscoring the need for globally representative genomic data. Additional complexity arises from non exonic variants, suballeles, and haplotype phasing, particularly in highly polymorphic genes such as CYP2D6. Pharmacogenomics is especially relevant in polypharmacy, where drug-gene and drug-drug-gene interactions significantly increase the risk of adverse outcomes. In parallel, polygenic risk scores (PRS) are emerging as promising tools to integrate the cumulative effect of multiple variants, although their clinical applicability remains limited by population biases and the scarcity of pharmacologically annotated datasets. International initiatives such as Clinical Pharmacogenetics Implementation Consortium (CPIC), Dutch Pharmacogenomics Working Group (DPWG), ubiquitous pharmacogenomics (U-PGx), Electronic Medical Records and Genomics Network (eMERGE-PGx), and Testing for Preventing Adverse Drug Reactions (PREPARE) are accelerating the translation of pharmacogenomic knowledge into clinical practice. As additional sources of variability are incorporated and multi omics approaches expand, pharmacogenomics is poised to enhance therapeutic precision, reduce adverse events, and improve clinical outcomes, provided that its implementation is accompanied by robust evidence generation, professional training, patient education, and effective integration into healthcare systems.