Precision pharmacotherapy is often represented as a progression from genotype to phenotype, exposure, and dose. That sequence is useful but incomplete because the genome is comparatively stable whereas the pharmacological system surrounding it is not. Enzyme and transporter activity can be modified by inhibitors, inflammatory signaling, frailty, organ function, pregnancy, and treatment-mediated physiological change. Drug exposure may consequently diverge from the value anticipated from genotype alone, while pharmacodynamic sensitivity can vary independently of exposure. A clinically useful precision model should therefore distinguish durable genomic information from functional phenotype, changing physiological state, drug interactions, measured or predicted exposure, and response susceptibility. This Systems Perspective develops a proposed exposure–response architecture in which genotype functions as an important prior rather than a contemporaneous assay of whole-patient pharmacology. The framework treats discordance between genomic expectation and observed treatment behavior as information requiring reconciliation rather than as evidence that either genomic or phenotypic data should automatically dominate. It further distinguishes starting-dose prediction from longitudinal dose updating and separates pharmacokinetic uncertainty from pharmacodynamic uncertainty. The proposed model is intended as a conceptual basis for integrating pharmacogenomics with repeated clinical information, model-informed dosing, therapeutic drug monitoring, and decision-support systems. Its value remains conditional on drug-specific evidence, measurement quality, temporal resolution, population transferability, and prospective validation.
IJPRAS
