New Horizons in the Impact of Frailty on Pharmacokinetics: Latest Developments

Sarah N. Hilmer; Carl M.J. Kirkpatrick


Age Ageing. 2021;50(4):1054-1063. 

In This Article

Abstract and Introduction


Frail older people have a high prevalence of drug use and are susceptible to adverse drug reactions. The physiological changes of frailty are likely to affect pharmacokinetics and pharmacodynamics. We reviewed the methods and findings of published studies of pharmacokinetics in frailty. Nine studies describing pharmacokinetics and an additional three of pharmacokinetic pathways in frail older people were identified. Most pharmacokinetic studies investigated a single administration of a medication, dose or formulation, in small populations, often with limited representation of males or females, and applied variable definitions of frailty. Pharmacokinetic sampling designs generally utilised saturated sampling followed by analysis based on the trapezoidal rule for area under the curve, with more recent studies using sparser sampling and more sophisticated modelling to obtain individual and population values of all pharmacokinetic parameters. Overall, the pharmacokinetic studies reported only small changes in some parameters for some drugs with frailty, with the most consistent change reduced hepatic clearance in frail older people. Recommendations for future studies of pharmacokinetics in frailty include (i) standard objective definitions of frailty; (ii) larger studies including people with mild, moderate and severe frailty; (iii) population pharmacokinetic modelling to allow sparser sampling and consideration of multiple influences on pharmacokinetics; (iv) physiologically based modelling as the physiology of frailty emerges and (v) longitudinal pharmacokinetic studies of chronic drug therapy from middle to old age and from robust to pre-frail to frail, including pre-clinical studies. These data, accompanied by pharmacodynamics data in frailty, will inform safe, effective prescribing for frail older people.


Frailty, where decline in function in multiple systems results in a state of vulnerability to stressors, is increasing globally with ageing of our population.[1,2] Risk factors for the onset or progression of frailty encompass sociodemographic (advanced age, female sex, ethnic minority, low education, low socioeconomic position, living alone, loneliness), clinical (multimorbidity and chronic diseases, obesity, malnutrition, cognitive impairment, depression and polypharmacy), lifestyle (physical inactivity, low protein intake, smoking, increased alcohol intake) and biological factors (inflammation, endocrine factors, micronutrient deficits).[2] Over the past two decades, objective measures of frailty have been conceptualised and validated, with most based on either the frailty phenotype (three or more of weakness, slow gait speed, low physical activity, exhaustion and unintentional weight loss) or the frailty index (continuous score 0–1 of deficit accumulation, considering at least 30 deficits across clinical, biological, functional and social domains).

Optimal prescribing for frail older people is not well understood. Guidance relies on applications of basic principles of good prescribing and patient centred, multidisciplinary geriatric care,[3] or expert consensus criteria.[4] Frail older people rarely participate in randomised clinical trials, excluded for reasons that include age, co-morbidity, co-medications or functional inability to participate.[5] For example, a retrospective analysis of participants in trials of hypertension treatment in older adults found that reduced frailty index score predicted eligibility.[6] Recent retrospective analyses of participants in clinical trials by frailty subgroup provide limited information, due to the lack of participants with moderate and particularly severe frailty.[7] Pharmacovigilance data form the majority of direct data in frail older people.[8] Compared to non-frail older people, frail older people use more medicines and have more exposure to high-risk regimens.[9,10] Even after controlling for increased utilisation, frail older people have a higher risk of adverse drug events and severe adverse drug events.[11] This may be because of the reduced resilience to external stressors that defines frailty. It could also be due to the effects of the physiological changes of frailty on pharmacology. Theoretical impacts of the biology of frailty on pharmacokinetics are shown in Table 1. An understanding of the pharmacokinetic changes that occur in frailty could inform extrapolation of clinical trial data to prescribing for frail older people.