PHARMACOGENOMIC INSIGHTS INTO PERSONALIZED DRUG THERAPY: INTEGRATING MOLECULAR GENETICS AND PRECISION MEDICINE FOR IMPROVED CLINICAL OUTCOMES

Abstract

Through an understanding of the role of inherited and acquired genetic variation in differences in drug metabolism, efficacy and toxicity, pharmacogenomics is changing the landscape of personalized drug therapy. In this review, the molecular and genetic basis of pharmacogenomic variability, clinically relevant biomarkers, enabling technologies, therapeutic applications, implementation pathways, and implications for clinical outcomes will be explored. Collectively, common variants, rare variants, copy-number variants, drug-target variation, and gene environment interactions contribute to pharmacokinetic (PK) and pharmacodynamic (PD) variability. Advances in targeted genotyping, next-generation and long-read sequencing, multi-omics, pharmacomicrobiomics, and artificial intelligence are expanding the ability to identify actionable biomarkers and predict individualized drug responses. The clinical use of genotype-based approaches is becoming increasingly apparent in cardiovascular medicine, oncology, psychiatry, HIV treatment, and transplantation, where genotype-based approaches can assist in drug selection, dose optimization, reduction of drug toxicity, and optimizing treatment response. Factors that continue to limit the translation to routine care include the availability of variable-strength evidence, cost of implementation, clinician preparedness, electronic health record integration, and population diversity. Further advances will require robust multi-gene models that have been validated, clinical decision support systems that can be interoperable across institutions, a more diverse population and the incorporation of genomic data with multi-omics and clinical data. Pharmacogenomics is thus an important avenue for improved precision prescribing, which is safer, more effective and more personalized.