The Pharmacology of Aging: Why Age Matters
Posted May 03, 2012
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.
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.
Use the tab above to find multimedia from this event.
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)
Hilmer SN, Mager DE, Simonsick EM, et al. A drug burden index to define the functional burden of medications in older people. Arch. Intern. Med. 2007;167(8):781-787.
Final concept paper E7(R1): studies in support of special populations: geriatrics. International Conference on Harmonization of Technical Requirements for Registrations of Pharmaceuticals for Human Use. In: Geneva, Switzerland: ICH Secretariat; 2008.
E7 studies in support of special populations: geriatrics questions & answers. International Conference on Harmonization of Technical Requirements for Registrations of Pharmaceuticals for Human Use. In: Geneva, Switzerland: ICH Secretariat; 2010.
Annegers JF, Hauser WA, Lee JR, et al. Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935–1984. Epilepsia. 1995;36(4):327-333.
Birnbaum AK, Hardie NA, Conway JM, et al. Valproic acid doses, concentrations, and clearances in elderly nursing home residents. Epilepsy Res. 2004;62(2-3):157-162.
Birnbaum AK, Conway JM, Strege MA, Leppik IE. Variability of carbamazepine and valproate concentrations in elderly nursing home residents. Epilepsy Res. 2012.
Cho S, Lau SWJ, Tandon V, et al. Geriatric drug evaluation: where are we now and where should we be in the future? Arch. Intern. Med. 2011;171(10):937-940.
Yu D, Corbett B, Yan Y, et al. Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer's disease. Neurobiol. Aging 2012.
Jenny Y. Chien
Aarons L, Karlsson MO, Mentré F, et al. Role of modelling and simulation in Phase I drug development. Eur. J. Pharm. Sci. 2001;13(2):115-122.
Kerbusch T, Wählby U, Milligan PA, et al. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Br. J. Clin. Pharmacol. 2003;56(6):639-652.
Ring BJ, Chien JY, Adkison KK, et al. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: Comparative assessement of prediction methods of human clearance. J. Pharm. Sci. 2011.
Jeremy D. Walston
Bandeen-Roche K, Walston JD, Huang Y, et al. Measuring systemic inflammatory regulation in older adults: evidence and utility. Rejuvenation Res. 2009;12(6):403-410.
Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 2001;56(3):M146-156.
Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients. J. Am. Coll. Surg. 2010;210(6):901-908.
Walston J, Fedarko N, Yang H, et al. The physical and biological characterization of a frail mouse model. J. Gerontol. A Biol. Sci. Med. Sci. 2008;63(4):391-398.
Molly E. Zimmerman
McCarthy LH, Bigal ME, Katz M, et al. Chronic pain and obesity in elderly people: results from the Einstein aging study. J. Am. Geriatr. Soc. 2009;57(1):115-119.
Sliwinski MJ, Hofer SM, Hall C. Correlated and coupled cognitive change in older adults with and without preclinical dementia. Psychol. Aging 2003;18(4):672-683.
Zimmerman ME, Brickman AM, Paul RH, et al. The relationship between frontal gray matter volume and cognition varies across the healthy adult lifespan. Am. J. Geriatr. Psychiatry 2006;14(10):823-833.
Seongeun (Julia) Cho, PhD
Seongeun Cho received her PhD in neuropharmacology from the Ohio State University College of Medicine. After completing a post-doctoral fellowship at University of Chicago, she joined Wyeth Neuroscience Research, where she led development of small molecules and therapeutic biologics for the treatment of neurological disorders. In 2009, she joined the FDA, Office of Clinical Pharmacology, and supported a review and pre-market approval of NDAs and BLAs for neurological products. Recently, Cho has taken a role as an enforcement lead for the Division of Bioequivalence and Good Laboratory Practice in Office of Compliance and is working on enforcement strategy and policy. She is a member of Scientific Interest Group and has authored numerous scientific and regulatory white papers.
Jennifer Henry, PhD
The New York Academy of Sciences
Jennifer Henry received her PhD in plant molecular biology from the University of Melbourne, Australia, with Paul Taylor at the University of Melbourne and Phil Larkin at CSIRO Plant Industry in Canberra, specializing in the genetic engineering of transgenic crops. She was then appointed as Associate Editor, then Editor, of Functional Plant Biology at CSIRO Publishing. She moved to New York for her appointment as a Publishing Manager in the Academic Journals division at Nature Publishing Group, where she was responsible for the publication of biomedical journals in nephrology, clinical pharmacology, hypertension, dermatology, and oncology. Henry joined the Academy in 2009 as Director of Life Sciences and organizes 35 – 40 seminars each year. She is responsible for developing scientific content in coordination with the various life sciences Discussion Group steering committees, under the auspices of the Academy's Frontiers of Science program. She also generates alliances with outside organizations interested in the programmatic content.
Darrell R. Abernethy, MD, PhD
Darrell R. Abernethy is responsible for leading the development of a pharmacological mechanism-based safety program in the Office of Clinical Pharmacology, in synergy with efforts in the Office of Surveillance and Epidemiology and other Offices and Centers at FDA. Abernethy brings more than 25 years of experience in medicine and pharmacology, including positions in academia, practice and research. Prior to joining the FDA he served as Chief Science Officer at USP. Abernethy earned his MD and PhD from the University of Kansas School of Medicine in 1976. In addition to his work at the FDA, he is currently a professor of medicine (geriatrics) and of pharmacology and molecular science at the Johns Hopkins University School of Medicine. Abernethy's training in Internal Medicine was at the University of Miami/Jackson Memorial Hospital, and his postdoctoral training in Clinical Pharmacology at Massachusetts General Hospital followed this. He is Board Certified in Internal Medicine and Clinical Pharmacology. He joined the faculty at Tufts–New England Medical Center as an Assistant Professor. Then, he was a professor at Baylor College of Medicine, Chief of the Division of Clinical Pharmacology and Professor of Medicine at Brown University School of Medicine, and then Francis Cabell Brown Professor of Medicine and Pharmacology and Director of the Division of Clinical Pharmacology at Georgetown University School of Medicine. Abernethy then joined the National Institute of Aging as Chief of the Laboratory of Clinical Investigation in the intramural research program.
Angela Birnbaum, PhD
Angela Birnbaum is an Associate Professor in the Department of Experimental and Clinical Pharmacology in the College of Pharmacy at the University of Minnesota. She is a co-founder of the Center for Clinical and Cognitive Neuropharmacology and the Pharmacometrics Division of the Center for Forecasting Drug Response. Her expertise and research interests focus on the clinical pharmacokinetics of antiepileptic drugs in special populations. She has been working in the pharmacokinetic analyses and modeling field for 16 years. Birnbaum is/has been principal investigator on grants funded by the National Institutes of Health investigating the effect of pharmacokinetics of antiepileptic drugs and outcome measures in elderly nursing home patients.
Jenny Y. Chien, PhD
Jenny Chien is Senior Research Advisor in Global Pharmacokinetics/Pharmacodynamics and Pharmacometrics at Eli Lilly and Company. Chien received her PhD in 1997 from the School of Pharmacy at the University of Washington in Seattle. She is a clinical team leader in the diabetes and metabolic disease therapeutic areas, utilizing drug–disease models, trial simulations and clinical utility decision tools to optimize drug candidate selections, development plans, study designs and dose-finding from preclinical to commercialization phase of drug development. Chien is also recognized for her expertise in the translational science of integrating physiologically-based and in vitro–in vivo approaches in the prediction of drug disposition and drug–drug interaction potentials in human. She has served as the chair of PhRMA PISC initiative on Human PK Prediction as well as a leader on several pharmaceutical industry and FDA sponsored initiatives to develop and apply predictive pharmacokinetic and drug–drug interaction methodologies. Chien is an affiliated faculty of the University of Washington, School of Pharmacy, and an Editor of the Journal of Pharmaceutical Sciences "Trends in Clinical Trials and Translational Medicine."
Jeremy D. Walston, MD
Jeremy Walston is the Raymond and Anna Lublin Professor of Geriatric Medicine. Walston received his medical doctorate from the University of Cincinnati and completed a General Internal Medicine Residency and Geriatrics Fellowship at the Johns Hopkins University. Since joining the Geriatric Medicine faculty, his major clinical focus has been on Geriatric rehabilitation medicine. He was the Medical Director of the Terrace Rehabilitation Unit for several years, and still regularly attends on that unit. His research interests have focused on the identification of physiological and molecular underpinnings of chronic disease, frailty, and late-life vulnerability. He provides ongoing aging research and academic career mentorship for several highly successful junior faculty, post-doctoral fellows, and graduate students in the Division and across the Johns Hopkins Medical Institutions. He leads the NIA-sponsored Johns Hopkins Older American Independence Center and is the PI of several other grants that focus on inflammation biology and late life decline. Walston is also a co-founder and co-director of the Biology of Healthy Aging Program. He holds a joint appointment in the School of Nursing where he regularly lectures on frailty and geriatric clinical care.
Molly E. Zimmerman, PhD
Molly Zimmerman received her PhD in clinical psychology from the University of Cincinnati. She completed a clinical neuropsychology internship and NIA T32 Institutional Research Training Program in Dementiaat Brown University. Zimmerman currently works in the Department of Neurology at the Albert Einstein College of Medicine where she serves as the Director of Neuropsychology for two NIA-funded program project grants on aging and dementia, the Einstein Aging Study and the Longevity Aging Study. Her research interests focus on age-related changes in cognition, sleep, and the experience of pain among older adults.
Kristen Delevich is a graduate student in the Watson School of Biological Sciences at Cold Spring Harbor Laboratory. Her work in Bo Li's laboratory focuses on the role of a schizophrenia susceptibility gene on synaptic physiology in the maturing rodent cortex. She earned her BS as a double-major in Neuroscience and Philosophy at the University of Pittsburgh. Her previous research has spanned from human to monkey to mouse brains. When she's not at the rig patch-clamping, you can find her at her home-base in Brooklyn.