Drug development and use in the elderly: search for the right dose and dosing regimen

Across the globe over the last few decades, there has been a remarkable increase in the proportion of the population which is elderly, and this trend is set to continue. Data from 10 countries that accounted for about 55% of the world population of 6079 million in the year 2000 provide an overview of this significant shift in demography. Table 1 summarizes the projections for the next 25 years. Hitherto, increases in life expectancy have been most obvious in the affluent countries; however, improvements in public health and disease control are also leading to increases in life expectancy in the less affluent countries. As a result of relatively larger increases in life expectancy at birth, significant shifts in demography are also expected in countries that are at present economically less affluent. The number of elderly people in the world is therefore expected to continue to increase for some considerable time. Interestingly, the most dramatic increases in the proportion of the population who are elderly are anticipated in countries where total populations are projected to decrease (such as Japan, Germany and Italy). The 2001 population census of the UK revealed that since the census of 1951, the proportion of elderly population above 65 years and 85 years has increased from 16% and 0.4% respectively to 21% and 1.9%, respectively. These changes in demography will have significant effects on the economics generally as well as on the provisions for healthcare. Cardiovascular and neurological diseases and cancers are the most prevalent in the elderly. These three groups of diseases account for about 54% of the total burden of disease in Europe in terms of disability adjusted life years. Of the total gross Hospital and Community Health Services expenditure of £31.9 billion in the year 2001–2002 in the UK, 13% was expended on people aged 65–74 years, 16% on those aged 75–84 years and 10% for people aged 85 years or more. Furthermore, about 55% of the community prescriptions during 2001 in the UK were dispensed for the elderly. Cardiovascular and psychoactive drugs accounted for more than 40% of these prescriptions. In view of many age-related changes in the pharmacokinetics and pharmacodynamics of a drug, the safe and effective prescribing of medicines in the elderly will continue to present a major challenge. This review provides an overview of the issues relevant to development and clinical use of drugs in the elderly population, with particular reference to determining the right dosage and dose regimen and the regulatory requirements that facilitate this process. It also examines whether, as a result of advancing age per se, the dosing regimens in the elderly and the frail elderly might be different from those in the non-elderly. Before discussing the impact of any age-related changes in drug response and the current regulatory framework supporting the development of drugs in the elderly, it is worth asking whether the medications already available are used appropriately in this population. The broad aims of treatment in this group are improving morbidity and prolonging survival without any adverse effect on quality of life. A number of studies have reported on the use of inappropriate medications in the elderly while others have focused on underutilization of appropriate medications. Such prescribing patterns have important consequences in terms of frequencies of adverse drug reactions (ADRs), hospitalizations and mortality in the elderly as well as implications for healthcare and economic resources. A PubMed search by the author in February 2004, using the combination of key words ‘inappropriate use of drugs’ and ‘elderly’, retrieved 372 citations (although each citation was not individually scrutinized). In one study of 603 hospitalized patients with a mean age of 79 years, a total of 376 patients (62%) were discharged on digoxin. There was no indication for its use in 223 (37%) patients. Half of the patients in whom digoxin was not indicated were actually given the drug. Furthermore, 38 (29%) of the 132 patients without an indication and not already on digoxin were initiated on it [1]. Onder et al. have reported that during of patients age 79 to or one or more medications as inappropriate on the of was the most used by digoxin and The particular drugs used from to and from to studies that a number of drugs are to the elderly. 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