Comparison of Inhaled Corticosteroids: An Update

H William Kelly, PharmD

Disclosures

The Annals of Pharmacotherapy. 2009;43(3):519-527. 

In This Article

Relative Potency of Inhaled Corticosteroids

It has been well established that chemical changes in the basic corticosteroid molecule produce significant differences in potency, usually measured as binding affinity at the glucocorticoid receptor. The relative receptor affinities are provided in Table 2.[2,7,9,10,11,12,13,14] The affinities have been compiled from numerous sources and compared with dexamethasone, which is given the arbitrary unit of 1. The relative binding affinities should not be interpreted as absolute differences in potency, as it is possible to have compounds with high binding affinity but without efficacy. Therefore, numerous laboratories also assess functional activity such as stimulation and suppression of gene activation; however, these studies also provide results that vary between laboratories.[15,16] The relative binding affinities correlate with relative potencies in carefully controlled clinical trials.[17] It is clear from the relative potencies that some drugs (beclomethasone dipropionate, ciclesonide) act as prodrugs and that their active metabolites (beclomethasone monopropionate and desisobutyryl-ciclesonide [des-ciclesonide]) provide most, if not all, of the clinical activity.

Potency does not affect the therapeutic index (topical efficacy to systemic activity ratio), and efficacy differences are simply overcome by administering equipotent doses.[1,2,9,10,11,12,13,14] However, potency does determine the efficacy of specific doses and so is one of the major determinants of the relative comparable doses shown in Table 1, along with delivery to the lung from the aerosol device.[1] The best test for comparing clinical potency would be a sensitive measure of asthma inflammation or activity that responded to at least a 2-fold difference in dosing and administration by delivery devices that deliver the same amount of drug in a uniform fashion. Unfortunately, we have neither of these conditions when comparing relative efficacy of the inhaled corticosteroids. For example, using the standard measures of efficacy, improvement in baseline lung function and reduction of the risk of asthma exacerbations, it is not possible to distinguish 2-fold differences in doses of the same inhaled corticosteroid delivered with the same aerosol delivery system.[18,19,20,21] Each device (MDI, DPI, NEB) delivers varying amounts of drug to the lungs of the patients, both intradevice (eg, fluticasone propionate DPI vs budesonide DPI) as well as interdevice and intradrug (fluticasone propionate DPI vs MDI).[22,23,24] Also, the addition of spacer devices to MDIs and use of facemasks with MDIs plus spacers or NEBs can substantially alter delivery.[24,25,26] Thus, the clinical comparative doses in Table 1 are based on large or multiple direct comparative clinical trials.

Some have argued that the standard measures of improvement in baseline lung function, symptom scores, and prevention of exacerbation are too insensitive to detect real differences in potency. Other measures, such as improvement in bronchial hyperresponsiveness (BHR) to challenges of exercise, methacholine or adenosine monophosphate, or biomarkers of airway inflammation such as fraction of exhaled nitric oxide and sputum eosinophils, have been posited as more sensitive markers of inhaled corticosteroid response.[27,28,29] Although the response of these markers to changing doses of inhaled corticosteroids has yet to be fully established,[30] inhaled corticosteroids do produce a more rapid response in these measures so they may be useful for short-term screening studies to establish initial doses for comparing these drugs.[4,27,28,29,30,31] Measures of BHR change rapidly, but they also continue to improve over a long period of inhaled corticosteroid administration.[1] It is likely that the use of numerous markers of efficacy is more appropriate, as they measure different aspects of asthma response. Sensitive markers of systemic activity, such as short-term growth, 24-hour urinary free cortisol, and 24-hour area under the curve (AUC0-24) for serum cortisol and serum osteocalcin, have been used to compare the potency of inhaled corticosteroids.[22,32] However, as these effects are highly dependent on the differences in the delivery and pharmacokinetics between the inhaled corticosteroid preparations, they are not useful for assessing relative potency, but can be used for determining relative systemic availability. The FDA recently began accepting studies using 24-hour urinary free cortisol as a marker to compare relative systemic availability of the inhaled corticosteroids.

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