0
Communications to the Editor |

Extra Fine Hydrofluoroalkane-134A Beclomethasone Aerosols To the Editor:To the Editor:: Selecting an Optimal Inhaled Steroid for an Individual Patient FREE TO VIEW

Norman L. Dean, MD, FCCP
Author and Funding Information

Affiliations: Pulmonary Clinic, North Carolina Correctional Institution for Women Chapel Hill, NC,  Dallas Asthma and Allergy Center Dallas, TX,  University of California, Los Angeles Los Angeles, CA

Correspondence to: Norman L. Dean, MD, FCCP, 109 Turnage Rd, Chapel Hill, NC 27514-9136; e-mail: mgdeanesq@aol.com



Chest. 1999;116(3):841-842. doi:10.1378/chest.116.3.841
Text Size: A A A
Published online

The importance of the development of a reformulation of beclomethasone dipropionate with hydrofluoroalkane (HFA)-134A into a solution that is capable of delivering a fine particle size with a mass median aerodynamic diameter of approximately 1 μm is cited in the article by Gross et al (February 1999)1and the related editorial by Tashkin (February 1999).2Administration of the extra fine corticosteroid aerosol results in a dramatic increase in lung deposition (51 to 56%) with a concomitant dramatic reduction in oropharyngeal deposition (28 to 30%), allowing for the use of considerably lower doses of beclomethasone to achieve efficacious end points.34

The key question is whether the enhanced lung deposition and systemic absorption translate into a more favorable therapeutic index (topical desired effects vs systemic unwanted effects). How does the HFA solution of beclomethasone compare with chlorofluorocarbon beclomethasone or other inhaled steroids such as budesonide dry powder delivered by the Turbuhaler (Pulmicort Turbuhaler; Astra AB; Westborough, MA), in regard to lipophilicity, water solubility, receptor binding activity, retention as well as uptake in airways, volume of distribution, terminal half-life, and systemic clearance rate?56 An updated state-of-the-art clarification of these pharmacokinetic parameters is needed for the current formulations and delivery devices of inhaled steroids.

Focused clinical longitudinal studies are also needed to compare the effects of HFA beclomethasone and alternative inhaled steroids on systemic effects that target the HPA adrenal axis, bone mineral density, bone turnover, ocular changes, linear growth rate in children, and ultimate height attained. The evaluation of data obtained from the focused longitudinal safety studies that are cited above, as well as explicit pharmacokinetic and pharmacodynamic profiles of specific inhaled steroids (incorporating specific delivery preparations) and efficacy data, will enable clinicians to select the optimal inhaled steroid and delivery device for an individual patient.7

Gross, G, Thompson, PJ, Chervinsky, P, et al (1999) Hydrofluoroalkane-134a beclomethasone dipropionate, 400μg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 μg, for the treatment of moderate asthma.Chest115,343-351. [PubMed] [CrossRef]
 
Tashkin, DF Extra-fine corticosteroid aerosols from hydrofluoroalkane-134a metered-dose inhalers: potential advantage and disadvantages.Chest1999;115,316-318. [PubMed]
 
Leach, CL, Davidson, PJ, Boudreau, RJ HFA-134a beclomethasone dipropionate (HFA-BDP): extra fine aerosol MDI delivers 57% lung deposition across inspiratory flow ranges of 43–163 LPM [abstract]. J Allergy Clin Immunol. 1998;;101(suppl 2) ,.:S63
 
Busse, W, Colice, G, Hannon, S, et al CFC BDP requires 2.6 times the dose to achieve equivalent improvement in FEV1as HFA-BDP [abstract]Am J Respir Crit Care Med1998;157,A405
 
Brattsand R. What factors determine anti-inflammatory activity and selectivity of inhaled steroids. Eur Respir Rev 1997; 7:50,356–361.
 
Miller-Larsson, A, Jansson, P, Runstrom, AB, et al Reversible fatty acid conjugation of budesonide results in a prolonged topical anti-inflammatory activity in airways as compared to fluticasone propionate [abstract]. Am J Respir Crit Care Med. 1997;;155 ,.:A353
 
Barnes, PJ, Pedersen, S, Busse, WW Efficacy and safety of inhaled corticosteroids: new developments.Am J Respir Crit Care Med1998;157,S1-S53. [PubMed]
 
To the Editor:

Dr. Dean raises a very interesting point regarding the clinical relevance of our finding that hydrofluoroalkane (HFA)-beclomethasone (BDP) extrafine aerosol provides the same degree of asthma control at a significantly lower dose compared with the conventional BDP inhaler (February 1999).1As it has been shown that the inflammatory process in the distal airways is more severe than in the proximal airways,2an anti-inflammatory medication that can reach this distal location should be more effective than one that cannot. Giving medication systemically is one way to achieve this goal, but a more direct approach that has been promoted over the last few decades is the use of an inhaled corticosteroid. The compound that we describe satisfies this requirement, unlike conventional BDP,3 and this characteristic needs to be factored into the desired effects of topical treatment.

The systemic effects of HFA-BDP extrafine aerosol and conventional BDP were measured in our study using morning plasma cortisol levels, and the results were comparable. In a study of similar design to ours, Davies et al4 compared doses of HFA-BDP extrafine solution, 800 μg/d, with conventional BDP, 1,500 μg/d. Although they found similar mean morning plasma cortisol levels, it was noted that a significantly greater number of patients receiving conventional BDP had levels below the normal range than those treated with the HFA-BDP extrafine aerosol.

Harrison et al5 have reported a 14-day study in steroid-naive patients who had asthma using the more sensitive marker of systemic activity of inhaled corticosteroids, 24-h urinary free cortisol (UFC) excretion levels. They found no differences in the mean change from baseline 24-h UFC excretion levels between the patients receiving HFA-BDP extrafine aerosol, 800 μg/d, and those receiving the same dose of chlorofluorocarbon-BDP, 800 μg/d.

With the results showing that BDP extrafine aerosol provides equivalent efficacy at a lower dose and with equivalent systemic safety at the same dose, the overall therapeutic ratio would seem more favorable than for the conventional BDP inhaler.

Administering the molecule as a solution changes the distribution of the medication because of the change in aerodynamic diameter of the particle but does not change the physical characteristics of the molecule itself (lipophilicity and receptor binding, among other characteristics). The effects of changing the particle size on the pharmacokinetic profile has been summarized by Seale et al.6We would agree with Dr. Dean that long-term comparative studies, such as those that he suggests and that were previously suggested by Barnes et al,7 will be necessary to better define the comparative strengths of various inhaled corticosteroid preparations and delivery devices.

References
Gross, G, Thompson, PJ, Chervinsky, P, et al Hydrofluoroalkane-134a beclomethasone dipropionate, 400 μg, is as effective as chlorofluorcarbon beclomethasone dipropionate, 800 μg, for the treatment of moderate asthma.Chest1999;115,343-351. [PubMed] [CrossRef]
 
Hamid, Q, Song, T, Kotsimbos, T, et al Respiratory pathophysiologic responses: inflammation of small airways in asthma.J Allergy Clin Immunol1997;100,44-51. [PubMed]
 
Marshall, BG, Wangoo, A, Shaw, RJ The in vivo effects of a formulation of inhaled beclomethasone (HFA-134a BDP, 3M Pharmaceuticals) on human alveolar macrophage function. Am J Respir Crit Care Med March. 1998;;157(B) ,.:A876
 
Davies, RJ, Stampone, P, O’Connor, BJ Hydrofluoroalkane-134a beclomethasone extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate at approximately half the total daily dose.Respir Med1998;92(suppl A),23-31. [PubMed]
 
Harrison, LI, Colice, GL, Donnell, D, et al Adrenal effects and pharmacokinetics of CFC-free beclomethasone dipropionate: a 14-day dose-response study.J Pharm Pharmacol1999;51,263-269. [PubMed]
 
Seale, JP, Harrison, LI Effect of changing the fine particle mass of inhaled beclomethasone dipropionate on intrapulmonary deposition and pharmacokinetics.Respir Med1998;92(suppl A),9-15. [PubMed]
 
Barnes, PJ, Pedersen, S, Busse, WW Efficacy and safety of inhaled corticosteroids: new developments.Am J Respir Crit Care Med1998;157(Number 3, Part 2),S1-S39
 
To the Editor:

Dr. Dean is correct in pointing out that a crucial question regarding the potential advantages and disadvantages of the extra-fine aerosol of beclomethasone dipropionate (BDP)- hydrofluoroalkane (HFA) is not simply whether this preparation has a similar efficacy to a lower dose of BDP-chlorofluorocarbon (CFC), but whether it has a higher or lower therapeutic index (ratio of therapeutic efficacy to side effects) in comparison with the latter preparation, as well as with other inhaled corticosteroids. Although a number of characteristics of the corticosteroid molecule itself (eg, lipophilicity and receptor binding activity among other characteristics) contribute to its anti-inflammatory potency and potential systemic effects, the reformulation of BDP in HFA would not be expected to alter these intrinsic properties. What appears to be unique about BDP-HFA, however, is its extra-fine particle size (median approximately 1 μm) that enhances deposition in the lower respiratory tract, including the peripheral airways, which, in contrast, are poorly penetrated by CFC-based suspension aerosols.

Regarding the question of therapeutic index, the potential clinical consequences of a greater deposition of BDP-HFA in the lung periphery include, on the one hand, enhanced efficacy in suppressing inflammation in smaller airways and, on the other hand, a possible predisposition to systemic side effects due to the greater bioavailability of BDP-HFA that occurs because of its absorption through the extensive pulmonary vascular bed in the distal regions of the lung.

To evaluate the possibility of uniquely efficacious and clinically meaningful effects of BDP-HFA on peripheral airways, focused short-term clinical trials incorporating sensitive measures of small airways function as well as appropriately designed long-term prospective studies are required.

Concerning systemic effects, limited pharmacokinetic data suggest that 200 μg BDP-HFA yields a slightly greater systemic bioavailability than does a therapeutically equivalent dose of BDP-CFC (400 μg), as suggested by the significantly higher maximum blood concentration of total BDP after inhaled doses of the HFA preparation.1On the other hand, in a 12-week randomized, double-blind study of 233 patients with moderately severe asthma, the safety profile of 800 μg BDP-HFA was superior to that of a therapeutically equivalent dose of BDP-CFC (1,500 μg), at least with respect to plasma cortisol levels.2 Clearly, further studies are needed to assess the relative therapeutic index of BDP-HFA in comparison with both BDP-CFC and other corticosteroid aerosols generated from different delivery devices using a variety of markers of systemic toxicity.

References
Seale, JP, Harrison, LI Effect of changing the fine particle mass of inhaled beclomethasone dipropionate on intrapulmonary deposition and pharmacokinetics.Respir Med1998;92(suppl),9-15
 
Davies, RJ, Stampone, P, O’Connor, BJ Hydrofluoroalkane-134a beclomethasone diproprionate extrafine aerosol provides equivalent asthma control to chlorofluorcarbon beclo-methasone diproprionate at approximately half the total daily dose.Respir Med1998;92(suppl),23-31
 

Figures

Tables

References

Gross, G, Thompson, PJ, Chervinsky, P, et al (1999) Hydrofluoroalkane-134a beclomethasone dipropionate, 400μg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 μg, for the treatment of moderate asthma.Chest115,343-351. [PubMed] [CrossRef]
 
Tashkin, DF Extra-fine corticosteroid aerosols from hydrofluoroalkane-134a metered-dose inhalers: potential advantage and disadvantages.Chest1999;115,316-318. [PubMed]
 
Leach, CL, Davidson, PJ, Boudreau, RJ HFA-134a beclomethasone dipropionate (HFA-BDP): extra fine aerosol MDI delivers 57% lung deposition across inspiratory flow ranges of 43–163 LPM [abstract]. J Allergy Clin Immunol. 1998;;101(suppl 2) ,.:S63
 
Busse, W, Colice, G, Hannon, S, et al CFC BDP requires 2.6 times the dose to achieve equivalent improvement in FEV1as HFA-BDP [abstract]Am J Respir Crit Care Med1998;157,A405
 
Brattsand R. What factors determine anti-inflammatory activity and selectivity of inhaled steroids. Eur Respir Rev 1997; 7:50,356–361.
 
Miller-Larsson, A, Jansson, P, Runstrom, AB, et al Reversible fatty acid conjugation of budesonide results in a prolonged topical anti-inflammatory activity in airways as compared to fluticasone propionate [abstract]. Am J Respir Crit Care Med. 1997;;155 ,.:A353
 
Barnes, PJ, Pedersen, S, Busse, WW Efficacy and safety of inhaled corticosteroids: new developments.Am J Respir Crit Care Med1998;157,S1-S53. [PubMed]
 
Gross, G, Thompson, PJ, Chervinsky, P, et al Hydrofluoroalkane-134a beclomethasone dipropionate, 400 μg, is as effective as chlorofluorcarbon beclomethasone dipropionate, 800 μg, for the treatment of moderate asthma.Chest1999;115,343-351. [PubMed] [CrossRef]
 
Hamid, Q, Song, T, Kotsimbos, T, et al Respiratory pathophysiologic responses: inflammation of small airways in asthma.J Allergy Clin Immunol1997;100,44-51. [PubMed]
 
Marshall, BG, Wangoo, A, Shaw, RJ The in vivo effects of a formulation of inhaled beclomethasone (HFA-134a BDP, 3M Pharmaceuticals) on human alveolar macrophage function. Am J Respir Crit Care Med March. 1998;;157(B) ,.:A876
 
Davies, RJ, Stampone, P, O’Connor, BJ Hydrofluoroalkane-134a beclomethasone extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate at approximately half the total daily dose.Respir Med1998;92(suppl A),23-31. [PubMed]
 
Harrison, LI, Colice, GL, Donnell, D, et al Adrenal effects and pharmacokinetics of CFC-free beclomethasone dipropionate: a 14-day dose-response study.J Pharm Pharmacol1999;51,263-269. [PubMed]
 
Seale, JP, Harrison, LI Effect of changing the fine particle mass of inhaled beclomethasone dipropionate on intrapulmonary deposition and pharmacokinetics.Respir Med1998;92(suppl A),9-15. [PubMed]
 
Barnes, PJ, Pedersen, S, Busse, WW Efficacy and safety of inhaled corticosteroids: new developments.Am J Respir Crit Care Med1998;157(Number 3, Part 2),S1-S39
 
Seale, JP, Harrison, LI Effect of changing the fine particle mass of inhaled beclomethasone dipropionate on intrapulmonary deposition and pharmacokinetics.Respir Med1998;92(suppl),9-15
 
Davies, RJ, Stampone, P, O’Connor, BJ Hydrofluoroalkane-134a beclomethasone diproprionate extrafine aerosol provides equivalent asthma control to chlorofluorcarbon beclo-methasone diproprionate at approximately half the total daily dose.Respir Med1998;92(suppl),23-31
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543