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Albuquerque, NM Perth, Western Australia
Correspondence to: Chet Leach, PhD, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108; e-mail: cleach{at}lrri.org
To the Editor:
Chrousos et al (July 2005)1 cited an article by this letter’s coauthor2 stating that "... as dry powder inhaler delivery of ICS results in higher lung deposition than delivery via CFC and HFA propellants... " The referenced article by LeSouef, "The Meaning of Lung Deposition," does not in any way state or imply that dry powder inhalers (DPIs) have greater lung deposition than propellant-driven inhalers. In fact, the article cited shows that lung deposition is unique to each device and drug combination. Furthermore, data from the LeSouef article is presented that shows that the specific hydrofluoroalkane (HFA) metered-dose inhaler (MDI) tested with and without add-on spacers demonstrated much higher lung deposition than the DPI assessed (ie, 60% HFA-MDI vs 40% for the DPI). In addition, the tested chlorofluorocarbon (CFC) MDI also showed higher lung deposition values than the DPI (ie, 45% for the CFC-MDI vs 40% for the DPI). The high HFA-beclomethasone dipropionate (BDP) MDI (QVAR; 3M Pharmaceuticals; St. Paul, MN) lung deposition values have been reproduced and published many times.345 To the best of our knowledge, no DPI has ever been demonstrated to achieve > 40% lung deposition, and indeed most marketed DPIs show values much < 30%.
We have also taken note of the claims1 of the association of mometasone DPI with a significantly lesser decrease in serum cortisol concentration area under the curve compared with the HFA-BDP, 200 µg MDI. The results seemed to show a numerically significant lack of cortisol suppression, but the results do not appear to be clinically significant. Given such small numbers of patients, it would seem appropriate to state the normal ranges of cortisol concentrations for all patients and then individually show the number of patients outside of the normal ranges and the degree to which they were outside of the normal ranges. For example, according to Table 2 in the article by Chrousos et al,1 the range at baseline for all patients was 998.1 to 4,286 nmol/L/24 h. The range for the HFA-BDP group at day 14 was 1,035 to 3,339 nmol/L/24 h. There was a 23% drop in the means from baseline to day 14, but all of the patients in the HFA-BDP group fell within the original normal baseline range. This hardly seems to be clinically significant, especially since there were no efficacy data given in this population. Thus, even if there was a clinically significant lack of a drop in cortisol with the mometasone DPI, the dose actually delivered to the patients was not shown to be efficacious in this study, whereas that dose of HFA-BDP has previously been shown to be efficacious.67 The assertions espoused by Chrousos et al,1 that DPIs demonstrate higher lung deposition than MDIs as well as the clinical significance of the lack of cortisol suppression, are therefore somewhat questionable.
References
Athens, Greece Kenilworth, NJ Liege, Belgium
Correspondence to: George P. Chrousos, MD, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, 115 27 Athens, Greece; e-mail: chrousge{at}med.uao.gr
To the Editor:
We thank Drs. Leach and LeSouef for their interest in our article,1 and we welcome the opportunity to comment on their observations. The issue of pulmonary drug deposition with various inhaled formulations is complex and influenced by many factors, as outlined by Dr. LeSouef in the article2 we cited. Chlorofluorocarbon (CFC) metered-dose inhalers (MDIs) are associated with low lung drug deposition (< 10 to 20%).23 Reduction of static charge within the spacer with a detergent can increase markedly the lung deposition via an MDI device.4 Hydrofluoroalkane (HFA)-beclomethasone dipropionate (BDP)-MDI devices achieve lung deposition rates of 37 to 56% in patients with asthma; younger individuals have lung deposition rates at the lower end of this range.356 Dry powder inhalers (DPIs) are associated with pulmonary deposition rates of up to 40%, or intermediate between results with CFC and HFA MDI devices.2 Despite different lung distribution rates, there is, however, no appreciable impact on the efficacies of inhaled corticosteroids delivered by DPI or MDI.7 Furthermore, the delivery of a greater fraction of the ex-actuator dose to the lung vs the oropharynx does not necessarily translate into lower systemic bioavailability. At one half the daily inhaled dose of BDP, HFA-MDI treatment was associated with a virtually identical mean percentage decrease from baseline in 24-h area under the curve serum cortisol as compared with CFC-MDI delivery. This occurred despite far less BDP being delivered to the oropharynx after HFA-MDI treatment. Despite presumably greater lung and lower oropharyngeal deposition of HFA-BDP, the corresponding hypothalamic-pituitary-adrenal (HPA)-axis suppression was significantly greater than with mometasone furoate (MF)-DPI. MF is a more potent steroid than BDP but has a low systemic bioavailability after inhaled dosing of approximately 1%.8 We would suggest that it is the high systemic bioavailability of BDP and its active metabolite9—irrespective of MDI delivery method—that determines its effects on the HPA axis.
Drs. Leach and LeSouef suggest that the results obtained in our study are not clinically significant, in part because no efficacy data were presented in parallel. The efficacy of MF-DPI at the dose used in our study (400 µg one puff qd) in the treatment of persistent asthma is well documented in peer-reviewed literature.1011 Our study was designed to examine the effects on the HPA axis of 14 days of treatment with MD-DPI, HFA-BDP, and CFC-BDP. Thus, our main end points were 24-h area under the curve serum cortisol and timed urinary-free cortisol collections, as these are appropriate tests for detecting HPA-axis impairment.12 From a purely endocrine perspective, it is important to be aware that a decrease of nearly one fourth in mean daily serum cortisol secretion can occur due to treatment with BDP, irrespective of HFA or CFC-MDI delivery. Given that MF-DPI, 400 µg one puff qd, is effective in the treatment of asthma, we believe that the finding of significantly lower HPA-axis suppression as compared with HFA-BDP and CFC-BDP is useful information when assessing the therapeutic profiles of inhaled corticosteroids for use in the clinical setting.
References
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