From cradle to cane—(Dis)similarities between paediatric and geriatric clinical pharmacology: A commentary arising from the 2024 International Union of Basic and Clinical Pharmacology (IUPHAR) World Smart Medication Day

The International Union of Basic and Clinical Pharmacology (IUPHAR) initiated the World Smart Medication Day in 2021 to raise awareness on safer and more effective use of drugs. The IUPHAR World Smart Medication Day is specifically targeted at students and early career researchers, to help foster clinical pharmacology development. It has covered aspects related to drug safety, pandemics, pharmacogenomics and precision medicine and—most recently in 2024—clinical pharmacology at the extremes of age: from cradle to cane.

Ensuring safe and effective pharmacotherapy at the extremes of age requires a thorough understanding of pharmacokinetics and pharmacodynamics (PK/PD) alongside key covariates. Additionally, specific considerations for pharmacovigilance and clinical trial design are essential to address the unique challenges in these populations. The Paediatric and Geriatric Pharmacology Committees of the Clinical and Translational Section of the IUPHAR each created 5-min educational videos on the three topics, which we are accessible at no cost on the IUPHAR website (Paediatric|IUPHAR—International Union of Basic and Clinical Pharmacology and Geriatric|IUPHAR—International Union of Basic and Clinical Pharmacology). During an international webinar on World Smart Medication Day 2024 (World Smart Medication Day|IUPHAR—International Union of Basic and Clinical Pharmacology), the videos were presented, and issues for paediatric and geriatric clinical pharmacology were compared and contrasted. Awards were also presented for the international student poster competition on clinical pharmacology at the extremes of age.

In this commentary, we highlight (dis)similarities of clinical pharmacology challenges and approaches for paediatric and geriatric patient populations, presenting opportunities to learn from each other to improve safe and effective medication use for patients at both extremes of age.

When considering PK and PD, it is quite intuitive that additional reflections are warranted when considering either paediatrics or geriatrics, because population-specific characteristics are important factors to consider to attain effective and safe pharmacotherapy.

The extensive weight range (<0.5 to >50 kg, >2 log value, even before considering obesity) within the paediatric field illustrates that extensive variability in both PK and PD should be anticipated. The main drivers hereby are maturational (age and weight), with a need for additional nuance in early infancy (postnatal, gestational or postmenstrual age, current vs. birth weight). These drivers obviously display collinearity. Allometry or body surface area (weight vs. size) is commonly considered to capture this collinearity, like the standard approach to report on glomerular filtration rate (mL/1.73m²).¹

This ‘size’ mediated variability is further extended by non-maturational covariates, like pharmacogenetics, drug–drug interactions or disease characteristics (like inflammation, critical illness and chronic kidney disease). It is important to realize that the impact of non-maturational covariates is not necessarily of the same magnitude as similar observations in adults.¹ Once developmental PK are well understood, it is equally important to consider developmental pharmacodynamics, including factors such as the adaptive immune system, neurological or psychiatric disorders and growth. Unfortunately, validated pharmacodynamic biomarkers as clinical substitutes in paediatric patients are currently limited.¹

Wide interindividual variability in PK and PD also occurs in geriatric patients. Some of this variability arises from changes related to ageing physiology, affecting body composition, hepatic and renal function, with less well-defined effects on pharmacodynamics. Frailty, which is a state of increased vulnerability due to loss of homeostatic reserve in several physiological systems, may also affect clinical pharmacology. While paediatric pharmacologists have nuanced approaches to ‘postnatal, gestational or postmenstrual age’, geriatric pharmacologists are working towards considering ‘chronological’ versus ‘biological’ age. Pharmacogenomic factors persist into old age, with no clear survival advantage for most different genotypes. Other ‘non-maturational covariates’ are increasingly complex in old age, with a lifetime of environmental exposures, and age-related increases in multimorbidity and polypharmacy all affecting clinical pharmacology, through their effects on organ function, drug interactions and the microbiome. All of these factors mean that interindividual variability between people of the same chronological age widens in old age. Current research is applying physiological-pharmacokinetic-pharmacodynamic modelling, including modelling frailty, to predict drug response and provide personalized medicine for geriatric patients.²

The core principles of adverse event assessment—evaluating seriousness, causality, severity and expectedness—remain similar for both paediatric and geriatric patients. However, the tools and patterns used differ significantly due to the unique vulnerabilities and characteristics of these populations. Given the influence of developmental PK/PD, pharmacovigilance patterns in children—including the type, frequency and severity of adverse events—are expected to differ significantly from those in adults. Consequently, paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development (e.g., neurodevelopment and puberty), clinical presentation of adverse drug reactions (ADRs), how they can be detected and assessed, besides some population-specific circumstantial factors (e.g., more frequent use of off-label/unlicensed drugs).³ This paediatric pharmacovigilance ‘flavour’ should be considered throughout the life cycle of medications, starting from preclinical data, to the development of any risk management plan, its integration in clinical trial protocols, to sufficiently detailed and targeted post-marketing pharmacovigilance approaches.³

Similarly, there are special considerations for pharmacovigilance in older people.⁴ The pattern of drug use differs in geriatric patients, with many drugs used for decades, providing opportunities to observe chronic effects, and with deprescribing providing insights on the effects of cessation. Geriatric patients often use drugs in polypharmacy combinations for management of multimorbidity, and pharmacovigilance can detect drug–drug and drug–disease interactions. Adverse drug events are more likely to be severe in geriatric patients, particularly in those who are frail, because their homeostasis and resilience are reduced. Attributing causality of adverse drug events is difficult because ADRs frequently manifest as non-specific geriatric syndromes, such as falls, confusion or incontinence. As described for children above, pharmacovigilance plans relevant to older people must be considered throughout the drug development life cycle.⁵ This is particularly important because of underrepresentation of older people with polypharmacy, multimorbidity and frailty in preregistration drug development trials, resulting in reliance on pharmacovigilance data to guide medication use.

From an equity approach, it is very fair to state that both children and older people are entitled to be treated with appropriately tested medications. Unfortunately, this is not yet the case, while trials in these populations also come with specific needs and characteristics.

Adapting trials to children relates—among others—to specific ethics (assent vs. consent, control arm), drug formulation aspects (dose flexibility), limited (sparse, low volume) blood sampling strategies, recruitment challenges or paediatric patient-relevant outcomes. There is also improved understanding that involving children and their parents from the trial design onwards is very effective and relevant, while the same holds true for the need of trial study teams to match paediatric needs.⁶ A recently agreed (August 2024) International Committee on Harmonization (ICH) statement on the use and harminization of paediatric extrapolation to support development and authorization of paediatric medications hereby reflects the shared opinion that extrapolation is a crucial tool to make paediatric drug development more effective and more timely.⁷ Population PK and physiologically based modelling should hereby facilitate simulations in the paediatric age range.⁸

Efforts to ensure representative recruitment of older people in clinical trials have highlighted similar challenges and strategies as those encountered in paediatric trials.^{9, 10} Older people, their carers and healthcare professionals have important roles in designing clinical trials that can recruit and retain geriatric patients and measure outcomes that matter to older people. Participant information, consent and study procedures need to accommodate people with sensory, functional or cognitive limitations. Exclusion criteria should not be unnecessarily restrictive on age, comedications or comorbidities. Like trials in children, appropriate formulations for a geriatric patient and use of sparse sampling with modelling are often required.

There are likely more similarities than initially expected at first glance, with a need to take paediatric and geriatric issues into account across all phases of drug development and use. Personalized medicine for paediatric and geriatric patients requires complex consideration of a range of factors, only one of which is their chronological age. These patients are vulnerable to ADRs, which may present atypically, requiring innovative approaches to pharmacovigilance. Similar principles can be applied at both extremes of age to achieve representative recruitment in clinical trials. We advocate for increased collaboration, shared methodological approaches and unified policy initiatives to enhance drug development, prescribing practices and patient outcomes from infancy to old age.

Karel Allegaert and Sarah N Hilmer both conceptualized, drafted, edited and approved the final manuscript.

K.A. chairs the Paediatric Committee and S. N. H. chairs the IUPHAR Geriatric Committee of the Clinical and Translational Section of the IUPHAR.