New productsEfficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma☆,☆☆,★,★★
Section snippets
Pathophysiology and scientific rationale
There is accumulating evidence that the airway inflammation and remodeling that characterize asthma occur in all parts of the airway from mainstem bronchi to bronchioles.4
Small airways have an internal perimeter of at most 2 mm. Changes in the function of these airways are difficult to assess because of the lack of specificity, sensitivity, and consistency of pulmonary function tests.9, 10 Consequently, the contribution of small airway dysfunction in asthma is unresolved. Nevertheless, newer
Pharmaceutics
The 2 main disadvantages of pMDIs over other inhalation devices are the relatively high throat deposition of drug and the cold-Freon effect (ie, the cold and uncomfortable feeling at the back of the throat on inhalation, which may prevent the patient from inhaling the full dose of corticosteroid). Both of these adverse effects arise from a high-velocity forceful blast impacting on the oropharynx.15 The need to change propellant provided the opportunity to improve pMDI technology because it
Lung deposition studies
Lung deposition studies have been performed by using radiolabeled aerosol BDP to determine the drug distribution within the lungs on inhalation. Subjects were required to demonstrate reproducible pMDI technique. The fine particle fraction (<4.7 μm) and mass median aerodynamic diameters for QVAR and CFC-BDP and radiolabeled analogs were measured by using the Anderson Cascade Impactor. Drug deposition was measured by using gamma scintigraphy.
In 16 patients with mild asthma receiving technetium
Pharmacokinetics
The potential influence of the greater lung delivery with QVAR compared with CFC-BDP on BDP pharmacokinetics was examined in 23 patients with mild asthma who completed an open, single-dose, randomized, 3-way, cross-over study.31 A serum assay for total beclomethasone (ie, BDP plus 17-beclomethasone monopropionate and 21-beclomethasone monopropionate metabolites) was used, which identified only low levels of beclomethasone in the serum, with the majority being BDP metabolites (over 90% of the
Efficacy
In view of the improved delivery characteristics of QVAR, resulting from the smaller droplet size and reduced impaction in the upper airway, the clinical efficacy of QVAR was evaluated at doses lower than those currently recommended for CFC-BDP.
The importance of treating the small airways
Small airway involvement has been demonstrated both physiologically and histopathologically (see “Pathophysiology and scientific rationale”), with evidence of small airway wall remodeling, but the clinical significance of these findings remains unclear.
Conventional CFC-based steroid-suspension aerosols may not adequately suppress inflammation in the small airway, presumably because of the reduced penetration of larger particles into these branches. Testing this hypothesis is difficult, and
Safety of QVAR
Because QVAR is a new formulation, the safety and tolerability of both the propellant and active constituent have been extensively monitored. However, because BDP is already well characterized as a result of its wide clinical use over the preceding 3 decades, it was not anticipated that any important issues would emerge for the active entity. Nevertheless, it was considered that there may have been changes in the tolerability profile relating to the reduced deposition in the oropharynx and the
Patient preferences
With the phasing out of CFC propellants, patients will be required to replace their existing pMDI with a CFC-free device. As part of the 12-month study described previously,41 patient opinions on the acceptability and the ease of switching from their CFC-BDP pMDI to QVAR pMDI were assessed by means of 2 questionnaires.57 The initial questionnaire concerned the CFC-inhaler used before the study and was completed after the run-in period. The follow-up questionnaire concerned the QVAR pMDI and was
Concluding remarks
The need to reformulate BDP has provided the opportunity to improve current therapies. With traditional CFC-BDP, where most of the drug is deposited in the oropharynx and is swallowed, studies now suggest that airway inflammation may not have been adequately treated. The findings that a lower daily steroid dose in QVAR is associated with improved delivery, even when discoordination is present, as well as comparable efficacy, tolerability, and no change in adrenal suppression up to 640 μg/d,
References (58)
- et al.
Inflammation of small airways in asthma
J Allergy Clin Immunol
(1997) - et al.
Variability of airway structure and inflammation in normal subjects and in cases of nonfatal and fatal asthma
Pathol Res Pract
(1996) - et al.
Molecular pathology of allergic disease. I. Lower airway disease
J Allergy Clin Immunol
(2000) - et al.
A new method to evaluate plume characteristics of hydrofluoroalkane and chlorofluorocarbon metered dose inhalers
Int J Pharm
(1999) Improved delivery of inhaled steroids to large and small airways
Respir Med
(1998)- et al.
Cough and wheezing from beclomethasone aerosol
Chest
(1987) - et al.
Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices
Chest
(1998) - et al.
Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant
J Allergy Clin Immunol
(1999) - et al.
Hydrofluoroalkane-134a beclomethasone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma
Chest
(1999) - et al.
Efficacy of chlorofluorocarbon-free beclomethasone dipropionate 400 micrograms/day delivered as an extrafine aerosol in adults with moderate asthma
Respir Med
(1998)
Clinical pharmacology of corticosteroids in bronchial asthma
Pharmacol Ther
Hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate at approximately half the total daily dose
Respir Med
Safety of long-term treatment with HFA albuterol
Chest
Safety of hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol
Respir Med
Acute safety of beclomethasone dipropionate in a new CFC-free propellant system in asthmatic patients
Respir Med
The comparative safety and efficacy ratio of HFA-BDP
Respir Med
Inhaled corticosteroids for adult asthma: impact of formulation and delivery device on relative pharmacokinetics, efficacy and safety
Respir Med
Inhaled corticosteroids and the hypothalamic-pituitary-adrenal (HPA) axis: do we understand their interaction?
Respir Med
The effects of inhaled glucocorticoids on bone mass and biochemical markers of bone homeostasis: a 1-year study of beclomethasone versus budesonide
Neth J Med
Switching from chlorofluorocarbon-beclomethasone dipropionate to a hydrofluoroalkane-134a beclomethasone dipropionate metered dose inhaler: study of patient preferences
Curr Ther Res
Inhalers and nebulizers: which to choose and why
Respir Med
National Heart, Lung and Blood Institute. Expert Panel Report 2. Guidelines for the diagnosis and management of asthma
The Montreal Protocol on substances that deplete the ozone layer. Final Act (Nairobi: UNEP, 1987)
Federal Register
Why the environment matters
Br J Clin Pract
The structure of large and small airways in nonfatal and fatal asthma
Am Rev Respir Dis
Division of Pulmonary and Allergy Drug Products. Points to consider for the clinical development programs for MDI and DPI prducts
Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone
Eur Respir J
Small airways: a time to revisit?
Thorax
Assessment of airway inflammation in asthma
Am J Respir Crit Care Med
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2021, European Journal of Pharmaceutical SciencesSmall airway dysfunction may be an indicator of early asthma: findings from high-resolution CT
2019, Annals of Allergy, Asthma and ImmunologyCitation Excerpt :Further research indicates that pathological abnormalities in the peripheral bronchioles and small airway dysfunction can be detected in patients with asthma regardless of severity and treatment stage.10–12 Moreover, treatment with small particle inhaled corticosteroids is more effective than with large particle inhaled corticosteroids.13–16 Increasing attention is now focused on the role of the small airways in asthma, and small airway dysfunction is now considered a distinct clinical phenotype or a sensitive indicator of early disease.17
Comparative efficacy and tolerability of beclomethasone/formoterol and fluticasone/salmeterol fixed combination in Taiwanese asthmatic patients
2018, Journal of the Formosan Medical AssociationDexamethasone palmitate large porous particles: A controlled release formulation for lung delivery of corticosteroids
2018, European Journal of Pharmaceutical SciencesReal-Life Outcomes for Patients with Asthma Prescribed Spacers for Use with Either Extrafine- or Fine-Particle Inhaled Corticosteroids
2017, Journal of Allergy and Clinical Immunology: In Practice
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Editor ’s note: This article initiates a series of special contributions to The Journal of Allergy and Clinical Immunology that will address state-of-the-art topics and concepts in the use of new medications/devices for the treatment of allergic and immunologic diseases. These New Products articles will appear regularly in the next several volumes. To ensure that statements of efficacy are evidence-based and there is no commercial bias, each of these articles will be critically reviewed by 2 clinical researchers and/or Editorial Board members who have not been associated with development of the new product.
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The authors disclose that they have served as consultants to 3M and have received grant support in the past to investigate QVAR’s mechanisms of action and clinical efficacy. They have prepared this report to present factual, unbiased information and attest that their associations with the developers of QVAR have not influenced this report, nor do they constitute commercial or personal conflict of interest.
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Sponsored by an unrestricted educational grant from 3M Pharmaceuticals, St Paul, Minn.
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Reprint requests: J. A. Vanden Burgt, 3M Center, St Paul, MN 55144-1000; fax, 651-737-7776; e-mail, [email protected].