Original article
Intervention
Characterization of respiratory deposition of fluticasone-salmeterol hydrofluoroalkane-134a and hydrofluoroalkane-134a beclomethasone in asthmatic patients

https://doi.org/10.1016/j.anai.2012.01.010Get rights and content

Abstract

Background

Fixed combination fluticasone-salmeterol is the most used anti-inflammatory asthma treatment in North America, yet no studies report the actual respiratory tract dose or the distribution of drug within the lungs. Inflammation due to asthma affects all airways of the lungs, both large and small. Inhaled steroid delivery to airways results from a range of drug particle sizes, with emphasis on smaller drug particles capable of reaching the peripheral airways. Previous studies suggested that smaller drug particles increase pulmonary deposition and decrease oropharyngeal deposition.

Objectives

To characterize the dose of fluticasone-salmeterol hydrofluoroalkane-134a (HFA) (particle size, 2.7 μm) delivered to asthmatic patients and examine the drug distribution within the lungs. The results were compared with the inhalation delivery of HFA beclomethasone (particle size, 0.7 μm).

Methods

A crossover study was conducted in asthmatic patients with commercial formulations of fluticasone-salmeterol and HFA beclomethasone radiolabeled with technetium Tc 99m. Deposition was measured using single-photon emission computed tomography/computed tomography gamma scintigraphy.

Results

Two-dimensional planar image analysis indicated that 58% of the HFA beclomethasone and 16% of the fluticasone-salmeterol HFA were deposited in the patient's lungs. The oropharyngeal cavity and gut analyses indicated that 77% of the fluticasone-salmeterol HFA was deposited in the oropharynx compared with 35% of the HFA beclomethasone.

Conclusions

The decreased peripheral airway deposition and increased oropharyngeal deposition of fluticasone-salmeterol HFA was a result of its larger particle size. The smaller particle size of HFA beclomethasone allowed a greater proportion of lung deposition with a concomitant decrease in oropharyngeal deposition.

Introduction

The National Asthma Education and Prevention Program guidelines call for the use of monotherapy of an inhaled steroid along with a short-acting β-agonist as needed for the initial treatment of mild to moderate persistent asthma.1 However, in the United States, contrary to the guidelines, nearly 70% of patients in this category are prescribed combination products as first-line therapy.2 Recently, the US Food and Drug Administration provided further guidance regarding treatment of persistent asthma and placed emphasis on the use of single-agent inhaled corticosteroids as first-line therapy. The Food and Drug Administration has further recommended limiting the long-term use of long-acting β-agonists with or without an inhaled corticosteroid.3 The question arises as to whether differences exist between particle sizes of combination products vs monotherapies that may affect safety and efficacy.

Fluticasone-salmeterol is the most prescribed fixed-combination anti-inflammatory inhaled product in North America, yet no published studies have characterized the actual dose of drug delivered to the respiratory tract of the patients or the distribution of drug within the lungs. Fluticasone-salmeterol hydrofluoroalkane-134a (HFA) is a metered-dose inhaler combination product that is classified as a drug suspension product. Such products rely on physical micronizing of the solid drug particle to as low a size as practical to reach the lungs and avoid oropharyngeal deposition. However, there is a physical limit to the particle size to which it can be micronized. Fluticasone-salmeterol HFA delivers a mean particle size of approximately 2.7-μm mass median aerodynamic diameter. Previous studies have shown that similarly sized fluticasone propionate chlorofluorocarbon (Flovent; GlaxoSmithKline, Research Triangle Park, North Carolina; particle size, 2.6 μm) delivered 13% of the drug to the lungs with comparatively little penetration to the peripheral lung regions.4 The remaining delivered dose was deposited in the oropharynx.

More recent technology has enabled some steroids to be formulated as a solution product wherein the steroid is dissolved in the propellant, and particles much smaller than those used in traditional suspension technology can be generated by adjusting the droplet size of the spray. Thus, particle sizes more suited for total lung penetration could be produced. This smaller particle has the added benefit of reducing oropharyngeal deposition.5 One such solution-based product is HFA beclomethasone (QVAR; Teva Specialty Pharmaceuticals LLC, Horsham, Pennsylvania). Previous studies have shown that HFA beclomethasone lung deposition ranged from 50% to 60% in adults, with penetration to all lung airways.[6], [7], [8], [9] A recent article described the importance of reaching all airways, including the small airways, to maximize treatment of inflammation sites due to asthma.10 The purpose of this open-label, crossover inhalation study in asthmatic patients was to characterize and compare the lung deposition of large particle fluticasone-salmeterol HFA with small particle HFA beclomethasone.

Section snippets

Radiolabeling

The radionuclide technetium T 99m (99mTc) was used to radiolabel formulations of HFA beclomethasone (QVAR) and fluticasone-salmeterol HFA (Advair HFA; GlaxoSmithKline) by the method for pressurized metered-dose inhalers (pMDIs) previously described.[4], [5], [6], [7], [8], [9] Briefly, the radiolabel was extracted out of the aqueous phase in 3-pentanone, which was then added to and evaporated from an empty canister. The contents of a filled canister containing the respective formulation were

Results

A 7-patient crossover study was conducted with commercial formulations of HFA beclomethasone (40 μg of beclomethasone dipropionate per actuation; QVAR) and fluticasone-salmeterol HFA (115 μg of fluticasone propionate and 21 μg of salmeterol per actuation; Advair HFA), each radiolabeled with 99mTc. Before patient dosing, a validation of the radiolabeling procedure was conducted to ensure the fidelity of the radiolabel to the respective drug. The results of these procedures showed that the

Discussion

The results illustrated by Figure 3 show that the small particle HFA beclomethasone formulation covered all airways in the lungs as opposed to the large particle fluticasone-salmeterol HFA formulation, which covered primarily the central airways, similar to the coverage obtained from chlorofluorocarbon-radiolabeled studies previously reported.4 This central deposition of large particle inhaled steroids is reflected by the results illustrated in Table 1 in which the C to P ratio was much higher

Acknowledgments

We thank Tamara Anderson, BS, for her invaluable technical assistance in conducting this study.

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Disclosures: Dr Leach has received research support and served on the speaker's bureau for Teva. Drs Kuehl and McDonald and Mr Chand have received research support from Teva.

Funding Sources: This study was funded by Teva Respiratory, LLC, Horsham, Pennsylvania.

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