Progress in geriatric pharmacology: Improving drug development, evaluation and use for ageing populations

Abstract

Ageing of the population worldwide, with the age-associated increase in multimorbidity, means that older people are now the major users of therapeutic drugs. Ensuring optimal drug development, evaluation and use by older people is an urgent priority for the global clinical pharmacology community. This special edition builds on presentations and discussions from a geriatric pharmacology seminar and a deprescribing workshop led by the International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee at the World Congress of Pharmacology, Glasgow, 2023. It includes reviews and translational research on some of the challenges and proposed solutions to providing quality use of medicines for older people.

Prescribing for older people has relied on evidence that may not be generalizable to them for far too long. Pre-clinical evidence has been limited to studies in young, male rodents. The commentary by Mitchell et al.¹ highlights the importance of pre-clinical drug evaluation in models that are representative of the older people who will use the drugs in terms of age, sex, frailty and drug exposures (e.g., polypharmacy). Similarly, there are international calls for representative recruitment of frail older people to clinical trials.² The review by Nguyen et al.³ identified clinical pharmacology studies that have conducted subgroup analyses according to frailty. The measurement and effect of frailty on efficacy and safety outcomes differed between drugs and studies.

Prescribers rely on the adage, ‘start low, go slow’ to select safe and effective drug doses for older adults, aiming to reduce the risk of adverse effects in this vulnerable population. However, frail older people are also vulnerable to disease and need drugs at doses that are effective. Pharmacometrics, encompassing physiological pharmacokinetic and pharmacodynamic modelling, can improve dose selection for such patients to optimize both safety and efficacy. Population pharmacokinetics and dose optimization of levofloxacin were applied to older patients with pneumonia in the study by He et al.⁴ This study highlighted some of the challenges of studies in older patients, such as obtaining accurate measures of weight, as well as the opportunities to apply this method using convenience sampling times. Pharmacometrics studies are now starting to investigate the effects of frailty on pharmacokinetics.

Another prescribing technique for older adults is the ‘geriatrician's salute’, also known as deprescribing.⁵ A major barrier to deprescribing in practice is a lack of evidence on its effects, making it difficult to practice ‘informed shared decision-making’. In this special issue, three complementary systematic reviews tackle this issue. The first has a disease focus, investigating the effect of deprescribing heart failure pharmacotherapy in older people.⁶ The second has a drug focus: deprescribing diuretics,⁷ which are most often prescribed for either heart failure or hypertension. Both reviews highlighted the lack of high-quality evidence on the feasibility, safety and tolerability of deprescribing, with no studies reporting on the outcomes according to frailty status of participants. The third examines the role of technology to enhance deprescribing. It found that existing applications focused on education and identified future opportunities to including interactive elements and artificial intelligence to enhance their utility in clinical care.⁸

Real-world data are critically important for understanding drug effects in older adults, who are under-represented in clinical trials. The review by Kalisch Ellett et al.⁹ describes novel, innovative methods in pharmacovigilance studies of drug use and outcomes in older people, including harnessing digital health technologies such as integration of electronic health records with routine adverse event reporting systems and the role of wearables. Older people residing in aged care homes are particularly under-represented in clinical trials and extremely vulnerable to medication-related harms. The review by Ea et al.¹⁰ highlights innovations and gaps in generating and translating evidence for safe and effective medication management in aged care homes through effective partnerships with aged care homes and provider organizations and by leveraging existing data and knowledge sharing through international platforms.

The papers in this special issue feature key opportunities for applying innovations in clinical pharmacology to improve prescribing for geriatric patients. Some key challenges identified are lack of translatable pre-clinical models and representative recruitment in clinical trials and some cohort studies. Multifactorial geriatric giants (e.g., falls, frailty and cognitive impairment) and other outcomes that matter most to older people (e.g., functional independence and social connectedness) must be addressed. These need to be routinely captured in baseline data and as outcomes in all phases of research. Even if they were captured, it is difficult to recognize adverse drug events and adverse drug withdrawal events when they present non-specifically as geriatric giants. Further innovations in each phase of the drug development and evaluation pathway, using bioinformatics to consider the complexity of older people, will enable personalized medicine for frail older people with a lifetime of exposures, multimorbidity, frailty and polypharmacy.

Sarah N. Hilmer is Chair of the IUPHAR Clinical and Translational Section and Chair of its Geriatric Committee. She proposed and chaired the geriatric pharmacology seminar and deprescribing workshop at the World Congress of Pharmacology, Glasgow, 2023. She spoke in the symposium on ‘Translational approaches to optimising pharmacotherapy for older people: Controversies in geriatric pharmacology’. Danijela Gnjidic presented in the deprescribing workshop at the World Congress of Pharmacology, Glasgow, 2023.