Pharmacogenomics in Geriatric Populations

Pharmacogenomics in geriatric populations addresses how inherited variation in drug response is expressed in older adults, whose physiology, organ function, and concurrent medications differ from those of younger patients. Ageing brings changes in body composition, hepatic and renal clearance, and target sensitivity, and older patients commonly take several drugs at once; these factors interact with germline pharmacogenomic variants and can shift the genotype-to-phenotype relationship through mechanisms such as drug-induced phenoconversion.

Definition

Pharmacogenomics in geriatric populations is the study of how heritable determinants of drug response interact with age-related physiological change, declining organ function, and polypharmacy in older adults to shape drug exposure, efficacy, and the risk of adverse effects.

Scope

The entry covers age-related pharmacokinetic and pharmacodynamic change, the interaction of these changes with germline pharmacogenes, and the role of polypharmacy and phenoconversion in older adults. It treats geriatric pharmacogenomics as a conceptual topic within special-population pharmacogenomics and is not a source of dosing or treatment guidance.

Core questions

• How do age-related pharmacokinetic and pharmacodynamic changes modify the effect of pharmacogenomic variants?
• How does polypharmacy in older adults alter the phenotype predicted by genotype through phenoconversion?
• When does ageing physiology, rather than genotype, dominate the drug-response phenotype?
• How well does pharmacogenomic evidence derived from younger adults apply to older patients?

Key concepts

• Age-related pharmacokinetic change
• Age-related pharmacodynamic change
• Polypharmacy
• Phenoconversion
• Reduced hepatic and renal clearance
• Genotype-phenotype discordance in ageing

Mechanisms

Drug handling changes with age through reduced lean body mass and total body water, altered protein binding, declining hepatic blood flow and metabolic capacity, and falling glomerular filtration, all of which tend to raise exposure to many drugs and their active metabolites. Pharmacodynamic sensitivity to some agents also changes. Against this background a germline pharmacogenomic variant continues to influence enzyme or transporter activity, but its observed effect is layered on top of age-related decline. A central mechanism in older adults is phenoconversion, in which co-administered inhibitors or inducers convert a genetically normal (extensive) metabolizer into a functionally poor or ultrarapid one; because polypharmacy is common with age, the gap between predicted genotype and observed phenotype can widen. Interpreting a geriatric pharmacogenomic result therefore requires accounting for both inherited capacity and the current physiological and drug-interaction context.

Clinical relevance

This topic helps clinicians and trainees understand why pharmacogenomic information in older adults is interpreted together with age-related physiology, organ function, and the patient's full medication list. It is reference-educational, describing how drug-response evidence is reasoned about in ageing, and is not a basis for individual dosing or treatment decisions.

Epidemiology

Older adults carry the same distribution of pharmacogene variants as the general population from which they come, but they bear a disproportionate burden of multimorbidity and polypharmacy, which increases the opportunity for drug interactions and phenoconversion to modify the apparent effect of a genotype.

Evidence & guidelines

Pharmacogenomic implementation resources such as PharmGKB and consortium guidelines apply across the adult age range, but dedicated evidence in the oldest and frailest patients is comparatively limited, so recommendations in this group are often extrapolated and interpreted with attention to concurrent physiological change and polypharmacy.

History

Geriatric clinical pharmacology established that ageing produces predictable but heterogeneous changes in drug disposition and response, motivating cautious dosing in older adults. As pharmacogenomics matured, attention turned to how inherited variation interacts with these age-related changes and with the polypharmacy characteristic of later life, giving rise to a distinct focus on pharmacogenomics in ageing.

Debates

Genotype versus phenoconversion as the driver of drug response in older adults

Because polypharmacy is common in older patients, an individual's measured drug-response phenotype may reflect drug-induced phenoconversion as much as germline genotype, and the relative weight of these factors in guiding interpretation is debated.

Key figures

• Arduino Mangoni
• Stephen Jackson
• Richard Weinshilboum
• William Evans

Seminal works

• mangoni-2003
• wang-2011
• evans-2003

Frequently asked questions

Does ageing change what a pharmacogenomic result means?

Ageing does not change the genotype, but age-related decline in organ function and pharmacodynamic sensitivity can alter how the genotype translates into drug exposure and effect, so results are interpreted within the older patient's physiological context.

What is phenoconversion and why does it matter in older adults?

Phenoconversion is when co-administered drugs make a genetically normal metabolizer behave like a poor or ultrarapid one; it matters in older adults because polypharmacy is common and can make the observed phenotype diverge from the predicted genotype.