The Pharmacology of Aging: Why Age Matters

Overview

Within the next two decades, the number of people aged 65 and older will double in the United States. Aging is a complex physiological process that can affect how bodies process and respond to medication, and clinical data increasingly suggest that when it comes to prescribing, one drug regimen does not fit patients of all ages. Older individuals have the highest disease burden and are prescribed the most medications, yet they are often left out of standard-setting clinical trials that put drugs on the market. At The Pharmacology of Aging: Why Age Matters symposium, presented by the Biochemical Pharmacology Discussion Group and the New York Chapter of the American Chemical Society, representatives from industry, government, and research communities met to discuss how to improve drug development strategies to better serve the geriatric population.

Seongeun Cho from the U.S. Food and Drug Administration introduced the day's topic by pointing out that clinical drug trials typically recruit relatively young, adult patients. We know that aging matters for drug response, but there is still much to learn concerning the mechanisms of how it matters. The day's symposium sought to open a dialogue about how to deliver patient-centric drug development for the elderly.

What separates an 80 year-old who plays golf daily from one who requires full-time care? We observe a range of health spans in late-stage life: from the vigorous and active, to the frail and home-bound. Jeremy Walston from Johns Hopkins School of Medicine is delving beneath the surface to understand the biology of frailty in order to improve patient care and extend healthy lifespan.

Clinically, frailty is defined as a geriatric syndrome of weakness involving weight loss and low activity. The outward signs of frailty reflect changes in the function of multiple internal systems and suggest a biological vulnerability to poor health outcomes. A study at Johns Hopkins Medical Center found that elderly patients who were identified as frail prior to surgery were much more likely to experience post-surgical complications. A frail assessment better predicted adverse outcomes than did many of the standard surgical risk assessment tools, suggesting that frailty captures an important biological feature that other risk assessment tools leave out.

Walston believes the leading candidate for this biological feature is inflammation: earlier studies linked inflammation and poor health in older adults, and proinflammatory markers are elevated in the frail, likely resulting from dysregulation of stress response pathways. When Walston screened the blood of older patients in a cardiac health study for markers of inflammation he that found five markers significantly associated with increased mortality. The 2 proteins that were most predictive of 10-year mortality were interleukin-6 and TNF-alpha, both pro-inflammatory cytokines produced by cells of the innate immune system. In order to study the biology underlying inflammation and frailty, Walston has developed a mouse model of frailty designed to mimic elderly patients’ susceptibility to inflammatory pathway activation. In the case of the frail mouse, this susceptibility is due to a lack of the anti-inflammatory signaling molecule, interleukin-10.

Just as our bodies age, so do our minds. As Molly Zimmerman from Albert Einstein College of Medicine explained, decline in cognitive performance and brain volume is to be expected in a healthy, aging individual. However, when this decline is accelerated, it can indicate that dementia looms on the horizon. Zimmerman investigated what factors set the trajectory for cognitive decline and whether physiological changes can accelerate a brain's aging.

A potential factor that could contribute to cognitive aging is pain. Chronic pain is defined as pain that persists beyond the normal tissue healing time; it can be thought of as a magnification of pain-related thoughts and perceptions after immediate, painful sensory input subsides. Zimmerman has tracked the influence of chronic pain on cognitive performance in a study of individuals aged 70 and over in the Bronx. Chronic pain is prevalent among the elderly; in her study, 52% of participants met the criteria for chronic pain. Zimmerman observed that participants who reported pain that interfered with their daily life were twice as likely to develop dementia and three times as likely to develop Alzheimer's disease. A potential culprit is the hypothalamic pituitary adrenal (HPA) axis, or stress axis, for short. Prolonged pain activates the HPA axis, leading to increased levels of stress hormones that have been shown to damage brain cells.

The discussion then shifted to how age-related health complications alter drugs' absorption, distribution, metabolism, and elimination, their so-called pharmacokinetics. Pharmacokinetics is an important consideration when determining a drug's dosage, and advanced age and the presence of other medications can make it difficult to predict pharmacokinetics. Angela Birnbaum from the University of Minnesota explained that older patients tend to absorb and distribute drugs across tissues to a lesser extent than younger patients do, but at the same time they are less efficient at metabolizing drugs and at clearing them from their systems. These opposing effects can make it difficult to predict how much of a drug will reach its site of action. In addition, the elderly often have comorbidities and are prescribed numerous medications that can further muddle the predictions of a drug's health impact.

Birnbaum is studying the impact of age on the pharmacokinetics of antiepileptics, a class of drugs that are primarily designed with the young in mind, but are increasingly prescribed to the elderly. Many might think of seizures as a disease of the young, but seizure incidence jumps after the age of 65. In fact, nearly 10% of patients in U.S. nursing homes take antiepileptic drugs. Dosing standards for antiepileptics are based on the drugs' pharmacokinetics in young people, and initial dose is set according to patients' weight. From there it is often a matter of trial and error to find a well-tolerated and effective dose.

The desired concentration for a chronically-dosed drug should be steady, such that the concentration never goes too high and causes side-effects or drops too low and stops being effective. Birnbaum reported that nursing home patients are often held at dosages of antiepileptic drugs that are below what is normally effective in younger patients, suggesting that the elderly may be more sensitive to them. When Birnbaum tracked serum drug concentrations, she found that the variability over time in total drug concentration was high within some elderly patients. Of particular interest are episodes when a patient's drug serum levels jumped from subtherapeutic to toxic concentrations over the course of several days. Health outcomes were not available at the time of the study, but Birnbaum plans to perform a study that will allow her to track the relationship between fluctuations in serum drug concentration and patient outcomes.

For the latter portion of the symposium, attendees heard from members on the frontlines of drug development in industry and government. Jenny Chen, a senior research advisor at Eli Lilly and Company, provided an overview of current drug development strategy and the current state of the inclusion of elderly in clinical trials. The good news is that the number of clinical trials that include participants over 65 has increased almost 6-fold in the past decade. However, there is still a lag in the assessment of drugs' pharmacokinetic properties in elderly patients.

One reason for a lack of elderly trial participants comes from health and safety concerns. In addition, it is difficult to assess the safety of a drug in a population with comorbidities and potential multiple drug interactions. It could be a mistake to derail a drug's development because of potentially confounded complications in older patients, especially if the drug is targeted to young patients. In general, the elderly aren't included in trials until later stages of drug development, even if the new drug will likely benefit them.

Drug companies are turning to quantitative and systems pharmacology approaches to mine the clinical data they have in order to predict the optimal dosing for the patients for whom they have limited data, e.g., the elderly. This approach allows pharmaceutical companies to develop informative dosing recommendations without the need for additional prospective trials, for which subpopulations such as the very elderly are difficult to recruit. These models incorporate key variables that determine drug pharmacokinetics, testing for interactions among variables. As an example in practice, the model found that both weight and age significantly affect the effective concentration of the blood-thinner prasugrel. Low weight and advanced age increased drug exposure, prompting label recommendations for lower doses in patients weighing less than 60 kg or older than 75 years of age.

Data comparing the inclusion of different age groups in the clinical trials for statin #1 show the discrepancy between the number of elderly included in a drug's development and the number who ultimately use the drug. Elderly individuals 75 and over made up only ~4% of participants in the new drug application (NDA) clinical trial for statin #1, while they accounted for 25% of all statin users at the time statin #1 hit the market. Abernathy said that statin #1 doesn't appear to be a special case: there is a general disparity in the inclusion of elderly patients in clinical trials and their use of new drugs. (Image courtesy of Darrell Abernethy)

Darrell Abernethy, the Associate Director for Drug Safety in the Department for Clinical Pharmacology addressed how the U.S. Food and Drug Administration is working to develop an evidence-based model to assess the relative risks and benefits of prescribing certain medications to the elderly. Echoing the other speakers' assessment, Abernathy said that because of comorbidities and multiple prescriptions, older patients are more likely to experience adverse drug events. This raises the question, when does a prescription regimen begin to cause more harm than good?

Abernethy and colleagues set out to investigate how increasing drug burden, an index that takes into account the number of drugs and their dosages, affects health. In their study, they took inventory of medications that patients in their 70s had taken in the past two weeks and then tested their physical and cognitive function. Among drug classes, anticholinergics—prescribed for a variety of conditions from gastrointestinal problems to respiratory problems—appeared to most negatively affect function, decreasing physical and cognitive measures with increasing drug burden.

To emphasize the impact of drug burden index on health: a one-point increase in the drug burden index altered the physical health score as much as three additional comorbidities. Further longitudinal studies have shown that this effect persists over a period of years: individuals with higher drug burden index at year one (baseline) were more likely to have reduced functional performance at year six. Abernethy noted that the FDA published guidelines as far back as 1989 concerning the inclusion of patients over 75 years old in pharmaceutical studies to test the consistency of treatment effect and safety profile. It is apparent that the amount of clinical trial data in the elderly needs to catch up with the appreciation for its necessity. On a positive note, Abernethy believes that the elderly population's participation in clinical trials will increase as the Baby Boomers age and seek better-informed drug treatment guidelines.

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Presentations available from:
Darrell R. Abernethy, MD, PhD (U.S. Food and Drug Administration)
Angela Birnbaum, PhD (University of Minnesota)
Jenny Y. Chien, PhD (Eli Lilly and Company)
Jeremy D. Walston, MD (Johns Hopkins University School of Medicine)
Molly E. Zimmerman, PhD (Albert Einstein College of Medicine)

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