The potential role of large language models in addressing phenoconversion in pharmacogenomics

Pharmacogenomics (PGx) is a cornerstone of precision medicine, enabling individualized drug therapy by identifying genetic factors that influence drug disposition and response. However, genotype-based predictions frequently fail to reflect actual drug-metabolizing capacity because enzyme activity can be modified by non-genetic factors, including concomitant medications, inflammation, organ dysfunction, aging, smoking, pregnancy, and other environmental influences. Phenoconversion can generate substantial discrepancies between genotype-predicted and observed metabolic phenotypes, contributing to adverse drug reactions, therapeutic failure, and reduced clinical utility of pharmacogenomic testing. The identification of phenoconversion remains challenging because the relevant determinants are often dispersed across multiple sources of information, including medication records, laboratory data, diagnostic information, and unstructured clinical notes within electronic health records. Recent advances in large language models (LLMs) offer new opportunities to address this limitation by retrieving, organizing, and contextualizing heterogeneous clinical and pharmacogenomic information. Beyond identifying drug-drug-gene and drug-gene-environment interactions, LLM-enabled systems may support dynamic phenotype assessment by modeling metabolic capacity as a continuously evolving characteristic rather than a static genotype-derived category and by identifying relevant modifiers even for drugs without actionable pharmacogenomic recommendations. This review examines the biological basis and clinical significance of phenoconversion and discusses the potential role of LLMs in bridging the gap between genetic predisposition and real-world drug response. We highlight the emerging concept of dynamic phenotype models that combine genetic, clinical, and environmental determinants of drug metabolism and may support more precise, context-aware pharmacotherapy.