Comparison of Inhaled Corticosteroids: An Update

H William Kelly, PharmD

Disclosures

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

In This Article

Effect of Delivery Devices

Delivery devices, in conjunction with patient technique, are the primary determinants of the dose delivered to the lungs of the patient.[1,24] Some of the changes in comparable doses in the new guidelines are based simply on changes in the delivery device (ie, budesonide Turbuhaler to budesonide Flexhaler, and flunisolide to a new hydrofluoroalkane [HFA]-propelled MDI) or new delivery information provided to the FDA (triamcinolone acetonide MDI).[1] The clinically comparable doses for all of the MDIs are based on their use without a spacer device, with the exception of fluticasone MDI in children 0–4 years old. How various spacer devices might affect relative comparable dosing has not been assessed. However, unless use of a spacer with an MDI produces a greater than 2-fold change in dose delivered, it is unlikely to make a clinically significant difference in efficacy. On the other hand, use of a spacer device may alter the systemic availability of an inhaled corticosteroid sufficiently to alter the therapeutic index.[22,23,24,25,26] For example, studies using chlorofluorocarbon (CFC)-propelled MDIs of beclomethasone dipropionate and fluticasone propionate have shown that use of a valved holding-chamber (VHC) spacer device decreased systemic activity of beclomethasone dipropionate by decreasing the amount of drug absorbed orally and increased the systemic activity of fluticasone propionate by increasing the amount delivered to the lung.[22,33] Most of the new inhaled corticosteroid HFA-MDIs have not been adequately studied clinically with VHCs, although some have been assessed with use of in vitro models.

The ongoing phase-out of CFC-propelled MDIs has spurred the development of many of the newer devices. Although the FDA required only albuterol CFC-MDIs to be phased out by December 2008, many manufacturers are phasing out their inhaled corticosteroid CFC-MDIs as well. The first inhaled corticosteroid HFA-MDI was beclomethasone dipropionate. Because that drug is soluble in HFA, a new MDI was developed that could produce particles with a much smaller mass median aerodynamic diameter of 1.1 µm, compared with 3.5–4.0 µm of the beclomethasone dipropionate suspensions in CFC-MDIs; this change significantly enhanced lung delivery of the drug.[34] The other inhaled corticosteroids in HFA-MDIs, also in solution, include ciclesonide and flunisolide (approved, but not currently available on the market). By contrast, fluticasone propionate is not soluble in HFA, so its HFA-MDI delivers slightly less fluticasone propionate compared with its CFC-MDI.[35,36] The 4- to 10-fold increase in lung delivery of beclomethasone dipropionate HFA-MDI translated into an only 2.6-fold increase in efficacy for improving lung function over the CFC-MDI in a large dose-response study.[37,38,39] This relative efficacy ratio holds up in trials comparing one-half the microgram dose of beclomethasone dipropionate by HFA-MDI with CFC-MDI and similar microgram doses of beclomethasone dipropionate by HFA-MDI with fluticasone propionate CFC-MDI.[34,40,41,42]

It has been suggested, but not proven, that the extrafine particles produced by HFA-MDIs of inhaled corticosteroids that are available as solutions may improve outcomes in patients as a result of greater penetration into the peripheral airways.[34] However, proving this hypothesis is difficult for 2 reasons: (1) the large increase in total lung delivery produced by the HFA-MDIs masking a specific increase in small airways delivery, and (2) the difficulty in specifically measuring small airways effects to distinguish between those and total effect. Two studies compared beclomethasone dipropionate HFA-MDI with fluticasone propionate administered by DPI in equal microgram daily doses.[43,44] Although each study concluded that HFA-MDI had greater efficacy in the small distal airways, they reported conflicting results of efficacy in lung function and the reduction in indices of airway inflammation (blood eosinophils and eosinophil cationic protein, and sputum levels of each). Fluticasone propionate administered by DPI delivers only 10–15% of the dose, which is much lower than even the fluticasone propionate MDI dose, so these small differences could be just a result of differences in total delivery of drug.

Another open-label study compared equal microgram amounts of beclomethasone dipropionate HFA-MDI (n = 20) with fluticasone propionate CFC-MDI (n = 10) in adults with poorly controlled asthma.[45] The addition of beclomethasone dipropionate HFA-MDI, but not fluticasone propionate CFC-MDI, increased measures of small airways function, including closing volumes and residual volumes as well as forced expiratory flow over 25–75% of vital capacity. However, forced expiratory volume in 1 second (FEV1) was also differentially improved, so it is not clear whether this is a specific small-airways effect or just greater total delivery. A more recent crossover comparison of beclomethasone dipropionate HFA-MDI 200 µg daily with fluticasone propionate DPI 200 µg daily in children aged 6–12 years failed to detect a difference in alveolar nitric oxide and bronchial nitric oxide flux, which are measures of small airways inflammation, as well as lung function measures.[46] Thus, improved small airways delivery resulting in improved overall efficacy of extrafine particle inhaled corticosteroid preparations remains a logical but unproven hypothesis.

The lack of proportionality between delivery and improvement in efficacy may be due to the heterogeneity of asthma severity in the patients included in the trials, the use of improvement in lung function, as measured by FEV1, as the primary outcome measure, or possibly, decreased conversion of beclomethasone dipropionate in the lung to its active monopropionate ester due to more rapid systemic absorption of the smaller soluble particles. Evidence for the latter effect comes from studies showing similar decreases in 24-hour UFC excretion produced by the HFA-MDI beclomethasone dipropionate at both one-half and at the same microgram dose of the CFC-MDI.[47] In addition, plasma AUCs for total beclomethasone were similar for one-half dose HFA-MDI and CFC-MDI and greater for the HFA-MDI at the same microgram dose. Thus, there was greater overall systemic availability of total beclomethasone from the HFA-MDI, as would be expected from the increased lung delivery. In contrast, the flunisolide HFA-MDI preparation delivers approximately 3 times the amount of flunisolide delivered by the CFC-MDI, and comparative clinical trials show that flunisolide HFA-MDI produces clinically comparable results to flunisolide CFC-MDI at one-third the labeled dose.[48,49]

The newest inhaled corticosteroid, ciclesonide, delivers approximately 50% of the ex-actuator dose to the lungs.[50] When compared with fluticasone propionate HFA-MDI, beclomethasone dipropionate CFC-MDI, and budesonide DPI, ciclesonide has similar efficacy when accounting for its relative potency (less than fluticasone propionate and greater than budesonide) and difference in delivery (greater than fluticasone propionate HFA-MDI and budesonide DPI).[2,3,4,5] Ciclesonide would be expected to provide equal efficacy to fluticasone propionate HFA-MDI in equivalent microgram doses based on its relative potency and delivery, but the formulations of ciclesonide 80 and 160 µg/puff do not match fluticasone propionate HFA-MDI at 44, 110, and 220 µg/puff. Therefore, comparisons at high doses have used 880 and 1760 µg/day of fluticasone propionate versus 1280 µg/day of ciclesonide; these dosing differences are not large enough to detect efficacy differences, but are large enough to show differences in sensitive measures of systemic availability (24-h UFC and serum cortisol AUC0-24).[51]

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