Drug Burden Index for international assessment of the functional burden of medications in older people.

Abstract

We thank Faure and colleagues for their interest in use of the Drug Burden Index (DBI). We share their desire to generalize this tool to allow it to be used more easily internationally. We wish to discuss their approach as outlined in the research letter, “A Standard International Version of the Drug Burden Index for Cross-National Comparison of the Functional Burden of Medications in Older People,”1 and to consider the implications not only for the proposed utility of comparing DBI between countries with existing formularies, but also for calculation of DBI in countries with limited national formularies, in which the tools to readily calculate a national DBI are not available. For countries with well-developed drug regulatory authorities and an advanced drug formulary structure, DBI as originally defined2 can be calculated from the formulary to measure exposure to medications with clinical anticholinergic or sedative effects. DBI has been calculated and validated against a range of clinical outcomes in different continents, countries, and settings, including the United States,2 Australia,3 the United Kingdom,4 and Finland.5 The DBI uses δ, the minimum registered or licensed dose on the national formulary, as an estimate of the dose required to provide 50% of the maximal effect (DR50). This is based on the pharmacological principle that a registered dose must have some efficacy and that the minimum dose is likely to have less than maximal efficacy. The actual DR50 for most therapeutic drugs in older adults is not known. There are some differences between countries in the minimum registered or licensed doses of medicines used in the calculations, which may be due to the effect of ethnicity on drug response6 or to other issues influencing the regulatory decisions. For example, diazepam has a minimum registered or licensed dose of 4 mg in the United States and 5 mg in Australia. In studies comparing DBI exposure between countries with well-developed national formularies, we agree that a consistent estimate of DR50 is required when differences between countries in minimum registered or licensed dose are unlikely to be related to the effect of ethnicity on pharmacological exposure and response. Using the median minimum registered or licensed dose for the countries studied should give a better estimate of DR50 than the World Health Organization (WHO) Defined Daily Dose (DDD)7 proposed in DBI-WHO1 for the reasons outlined below. For countries in which the WHO list of essential medications and WHO model formulary are used as primary resources to support and improve medication prescribing, we believe that calculation of DBI may best be performed using the WHO model formulary recommended adult starting dosage.8 Review of the WHO model formulary adult starting doses indicates that they rather closely reflect the minimum registered or licensed doses in the countries in which DBI has been validated against functional status and physical performance. This dose is, in most cases, substantially lower than the DDD7 substituted for δ in calculation of DBI-WHO.1 DDD is the average maintenance dose per day for a drug's main indication in adults and is not related to the drug's DR50. The DDD can differ markedly from the minimum registered dose for some, but not all, anticholinergic and sedative drugs that are commonly used in older people. For example, diazepam has a DDD of 10 mg, and the WHO model formulary recommended adult starting dosage is 5 mg. The finding that DBI-WHO produces a lower value for DBI is anticipated, because the effect of using a higher dose value is simply using a larger value for δ in the DBI equation. We cannot predict where the calculated value falls on the dose-response curve for these complex integrated functions or how this would affect the relationship between DBI and physical function. Therefore, we enthusiastically support the effort to make an index such as DBI available as widely as possible, because we strongly believe it has the potential to improve the prescribing of sedative and anticholinergic medicine in older adults worldwide. We would be delighted to work with Faure and colleagues to realize this potential. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Dr. Gnjidic is supported by a National Health and Medical Research Council Early Career Fellowship. Author Contributions: All authors contributed to the concepts in this letter and preparation of the manuscript. Sponsor's Role: None.