Discriminating measures of bronchodilator drug efficacy and potency.

Abstract

Bronchodilator drugs, used alone or in conjunction with inhaled corticosteroids or other anti-inflammatories, are essential to the effective management of asthma [1, 2]. The three main categories of effective bronchodilators are inhaled β2-adrenoceptor agonists and anticholinergics, and methylxanthines, particularly oral theophylline. The incidence of asthma continues to rise, however, enhancing the need to develop new bronchodilator drugs and products and to evaluate their therapeutic efficacy, potency and cost-effectiveness in relation to existing treatments [3]. The short-acting β2-adrenoceptor agonist salbutamol, in a pressurized metered dose inhaler (pMDI), has long been the most widely used bronchodilator, and a key factor influencing the requirement for new products is the phasing out of chlorofluorocarbon (CFC) pMDI propellants to curtail damage to the stratospheric ozone layer [4]. The pharmaceutical industry is also responding to a decade of off-patent availability of effective asthma drugs including salbutamol and the anticholinergic ipratropium bromide, which has encouraged the development of novel generic bronchodilator/inhaler device combinations [5]. This combination of factors has led to a pressing need to develop the most economical and precise methods of evaluating efficacy and potential clinical equivalence of inhaled bronchodilators with the traditional pMDI and current alternatives in order to satisfy both clinicians and regulatory authorities. Clinical equivalence of drugs relates to both potency and safety since the lowest effective dose must be used in order to minimize systemic side-effects. Measures of bronchodilator drug efficacy have in the past relied on direct measurement of the induced bronchodilatation by lung function testing. This often does not, however, allow potency discrimination between drug products, since a single dose can result in maximal bronchodilatation. This has led both clinicians and pharmaceutical professionals to develop more sensitive, repeatable, and therefore more discriminating methodologies employing alternative patient populations and alternative efficacy endpoints. Dose–response data are fundamental to the accurate measurement of both efficacy and systemic effects. Importantly, regulatory authorities are also addressing these issues [6–8]. This review focuses on β2-adrenoceptor agonist studies to highlight the discriminating measures of bronchodilator drug efficacy and potency which should enable a valid comparison of novel and traditional inhaled asthma treatments. (Measures and methodologies are summarized in Table 1.) Table 1 Comparison of methodologies for testing of bronchodilator efficacy.