From CYP450 pharmacogenomics to personalized medicine: clinical evidence, dosing guidelines, and future perspectives

Interindividual variability in drug response remains a critical challenge in contemporary pharmacotherapy, and cytochrome P450 (CYP450) genetic polymorphisms are a principal determinant of this heterogeneity. The CYP450 superfamily mediates the oxidative biotransformation of 70-80% of clinically prescribed medications. Genetic variants in key isoforms generate four distinct metabolizer phenotypes, producing up to 1000-fold interindividual differences in drug clearance that directly translate into therapeutic failure, adverse drug reactions, or life-threatening toxicity. This review critically synthesizes current mechanistic, clinical, and translational evidence on CYP450 pharmacogenomics, emphasizing genotype-guided individualized dosing across anticoagulation, antiplatelet therapy, oncology, neuropsychiatry, and solid organ transplantation. Guidelines from the Dutch Pharmacogenetics Working Group, the Clinical Pharmacogenetics Implementation Consortium, and the FDA are evaluated alongside phenotype-specific dosing algorithms. Emerging approaches are examined, including model-informed precision dosing, Bayesian pharmacokinetic forecasting, next-generation sequencing for haplotype resolution, and artificial intelligence-based clinical decision support. Persistent barriers, including phenoconversion by drug-drug interactions, under-representation of populations in pharmacogenomic datasets, and inconsistent guideline adoption, are critically appraised. PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for relevant literature published between 1978 and 2026. Coordinated global integration of CYP450 genotyping into routine clinical workflows is needed to advance the transition from reactive to preemptive, genuinely personalized pharmacotherapy.