Personalized Geriatric Pharmacotherapy: Pharmacogenomics, Polypharmacy, and Age-Related Pharmacokinetic and Pharmacodynamic Changes

Aging induces profound physiological changes that alter drug disposition and response, narrowing therapeutic windows and increasing susceptibility to adverse drug reactions (ADRs). This review synthesizes current evidence on age-related pharmacokinetic and pharmacodynamic changes, with a focus on pharmacogenomic determinants of drug response in older adults. Progressive decline in renal function, hepatic metabolic capacity, and alterations in body composition collectively necessitate age-appropriate dose adjustments. Polypharmacy, prevalent in community-dwelling and hospitalized older adults, compounds these challenges through drug–drug and drug–drug–gene interactions. Pharmacogenomic testing—particularly for CYP2D6, CYP2C19, CYP2C9, and SLCO1B1—offers a promising strategy to personalize therapy, while deprescribing frameworks provide practical approaches to mitigate medication-related risks. This review presents a comprehensive framework for understanding the mechanistic basis of altered drug response in older adults and proposes actionable strategies for optimizing pharmacotherapy in this vulnerable population.