PDF
ePub
Citation
Print
Abstract
The aging process is linked to changes in the physiological function of organs and changes in body composition that alter the pharmacokinetics of drugs and pharmacodynamic responses. Comorbidity and polypharmacy in the elderly decreases tolerability of drugs, leading to greater vulnerability to adverse drug reactions than that observed in younger adults. In geriatric pharmacotherapy, the general recommendation is dose reduction and slow titration, which is based on pharmacokinetic considerations and concern for adverse drug reactions, rather than clinical trial data. Older patients are under-represented in clinical trials. In the absence of evidence, extrapolation of risk–benefit ratios from younger adults to geriatric populations is not necessarily valid. Sound evidence through prospective clinical trials is essential, and geriatric societies, governments, and patient advocacy groups should collaborate to promote the inclusion of older people in clinical trials. It is believed that all involved in clinical trials have both an obligation and an opportunity to eliminate age discrimination in clinical trial practice.
References
1. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev. 2004; 56:163–184.
2. Mannesse CK, Derkx FH, de Ridder MA, Man in't Veld AJ, van der Cam-men TJ. Adverse drug reactions in elderly patients as contributing factor for hospital admission: cross sectional study. BMJ. 1997; 315:1057–1058.
3. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014; 13:57–65.
4. Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol. 2007; 21:217–230.
5. Unger JM, Coltman CA Jr, Crowley JJ, Hutchins LF, Martino S, Livingston RB, et al. Impact of the year 2000 Medicare policy change on older patient enrollment to cancer clinical trials. J Clin Oncol. 2006; 24:141–144.
6. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999; 341:2061–2067.
7. Statistics Korea, Population Projections for Korea: 2010–2060. Available at. http://kostat.go.kr/portal/english/news/1/9/index.board?bmode=download. &bSeq=&aSeq=253456&ord=2 Assessed October 15,. 2014.
8. Health Insurance Review & Assessment Service. Statistics of total medical expenses: 2008–2012. Seoul: Health Insurance Review & Assessment Service;2012.
9. International conference on harmonization of technical requirements for registration of pharmaceuticals for human use. Studies in support of special populations: geriatric E7. 1994.
10. Robertson DR, Wood ND, Everest H, Monks K, Waller DG, Renwick AG, et al. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol. 1989; 28:61–69.
11. Fülöp T Jr, Wórum I, Csongor J, Fóris G, Leövey A. Body composition in elderly people. I. Determination of body composition by multiisotope method and the elimination kinetics of these isotopes in healthy elderly subjects. Gerontology. 1985; 31:6–14.
12. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004; 57:6–14.
13. Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet. 2000; 38:271–290.
14. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002; 71:115–121.
15. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992; 44:275–283.
16. Hunt CM, Westerkam WR, Stave GM, Wilson JA. Hepatic cytochrome P-4503A (CYP3A) activity in the elderly. Mech Ageing Dev. 1992; 64:189–199.
17. Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging. 2001; 18:837–851.
18. Viallon A, Guyomarch P, Marjollet O, Belin M, Robert F, Berger C, et al. Creatinine clearance and drug prescriptions for the elderly. A study of 419 patients older than 70 years admitted through the emergency department. Presse Med. 2006; 35:413–417.
19. Vestal RE, Wood AJ, Shand DG. Reduced beta-adrenoceptor sensitivity in the elderly. Clin Pharmacol Ther. 1979; 26:181–186.
20. Kruse WH. Problems and pitfalls in the use of benzodiazepines in the elderly. Drug Saf. 1990; 5:328–344.
21. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003; 38:843–853.
22. Crowley JJ, Cusack BJ, Jue SG, Koup JR, Park BK, Vestal RE. Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men. J Pharmacol Exp Ther. 1988; 245:513–523.
23. Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother. 2013; 47:1478–1487.
24. Katz IR, Stoff D, Muhly C, Bari M. Identifying persistent adverse effects of anticholinergic drugs in the elderly. J Geriatr Psychiatry Neurol. 1988; 1:212–217.
25. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012; 60:616–631.
26. Gurwitz JH. Start low and go slow: dosing of antipsychotic medications in elderly patients with dementia. Arch Intern Med. 1995; 155:2017–2018.
27. Lister J. By the London post. Compliance in clinical care – Congress in Vienna – health services quangos. N Engl J Med. 1979; 301:1226–1227.
28. Hughes CM. Medication non-adherence in the elderly: how big is the problem? Drugs Aging. 2004; 21:793–811.
29. Bugeja G, Kumar A, Banerjee AK. Exclusion of elderly people from clinical research: a descriptive study of published reports. BMJ. 1997; 315:1059.
30. McMurdo ME, Witham MD, Gillespie ND. Including older people in clinical research. BMJ. 2005; 331:1036–1037.
31. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000; 50:7–33.
32. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol. 2005; 23:3112–3124.
33. Cherubini A, Oristrell J, Pla X, Ruggiero C, Ferretti R, Diestre G, et al. The persistent exclusion of older patients from ongoing clinical trials regarding heart failure. Arch Intern Med. 2011; 171:550–556.
34. Bernabei R, Gambassi G, Lapane K, Landi F, Gatsonis C, Dunlop R, et al. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA. 1998; 279:1877–1882.
35. Aapro MS, Köhne CH, Cohen HJ, Extermann M. Never too old? Age should not be a barrier to enrollment in cancer clinical trials. Oncologist. 2005; 10:198–204.
36. Denson AC, Mahipal A. Participation of the elderly population in clinical trials: barriers and solutions. Cancer Control. 2014; 21:209–214.
37. Rochon PA, Anderson GM. Prescribing optimal drug therapy for older people: sending the right message: comment on "impact of FDA black box advisory on antipsychotic medication use". Arch Intern Med. 2010; 170:103–106.
38. Crome P, Lally F, Cherubini A, Oristrell J, Beswick AD, Clarfield AM, et al. Exclusion of older people from clinical trials: professional views from nine European countries participating in the PREDICT study. Drugs Aging. 2011; 28:667–677.
39. Cherubini A, Del Signore S, Ouslander J, Semla T, Michel JP. Fighting against age discrimination in clinical trials. J Am Geriatr Soc. 2010; 58:1791–1796.
40. Barron JS, Duffey PL, Byrd LJ, Campbell R, Ferrucci L. Informed consent for research participation in frail older persons. Aging Clin Exp Res. 2004; 16:79–85.
41. Tinetti ME, Bogardus ST Jr, Agostini JV. Potential pitfalls of disease-specific guidelines for patients with multiple conditions. N Engl J Med. 2004; 351:2870–2874.
Table 1.
Pharmacokinetic changes in the elderly
Table 2.
Selected pharmacodynamic changes in the elderly (quoted from Ref. 12)
Table 3.
Selected barriers and solutions for participation of the elderly in clinical trials (quoted from Ref.36)
XML Download