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Therapeutic ratio of inhaled fluticasone
  1. BRIAN J LIPWORTH
  1. Asthma and Allergy Research Group
  2. Department of Clinical Pharmacology
  3. Ninewells Hospital and Medical School
  4. University of Dundee
  5. Dundee DD1 9SY
  6. UK
    1. RONALD J MEIJER,
    2. HUIB A M KERSTJENS,
    3. DIRKJE S POSTMA
    1. Department of Pulmonary Diseases
    2. University Hospital Groningen
    3. Groningen, The Netherlands

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      I read with interest the recent article by Meijer and colleagues on the effects of inhaled fluticasone and prednisolone on clinical and inflammatory parameters in patients with asthma.1 Rather than focusing on the differences between oral and inhaled corticosteroid, I believe that a more important finding is the effect of a fourfold increase in the dose of fluticasone on the therapeutic ratio. For airway parameters there were no significant differences in the effects on bronchial hyperresponsiveness to methacholine and adenosine monophosphate or on sputum eosinophils between fluticasone in doses of 500 μg and 2000 μg per day. However, for systemic bioactivity markers there were significant differences between the two doses of fluticasone on serum cortisol levels and blood eosinophils. Taken together these findings suggest that, at least for effects on airway hyperresponsiveness and inflammation, the therapeutic ratio for fluticasone declines sharply above a watershed dose of 500 μg per day. This result is perhaps not surprising, given the high glucocorticoid topical potency for in vitro anti-inflammatory activity with fluticasone.2

      It is also important to point out that the study by Meijeret al was performed using fluticasone delivered via a Diskhaler dry powder inhaler device, which delivers a twofold lower respirable fine particle dose than a fluticasone propionate pressurised metered dose inhaler.3 This is due to the larger particle size from the fluticasone dry powder inhaler. Hence, increasing the nominal dose of fluticasone dry powder may result in a proportionately greater delivery of larger particles to the central airways and consequently to a less than expected impact on small airway inflammation. The lower fine particle dose of fluticasone dry powder will also result in reduced lung bioavailability, as shown by a fivefold lower degree of adrenal suppression compared with the same nominal dose of fluticasone delivered via a pressurised metered dose inhaler with spacer device.4 The use of fluticasone in a dose of 500 μg/day via a dry powder inhaler would therefore explain the absence of any significant suppression of blood eosinophils or serum cortisol in their study. This does not mean that fluticasone propionate dry powder in a dose of 500 μg/day is not systemically bioavailable, as recently published data with this dose of fluticasone given via a Diskhaler reported significant suppression of 24 hour urinary cortisol excretion (33% reduction) and peripheral blood lymphocyte glucocorticoid receptor mRNA expression (71% reduction) during steady state dosing in asthmatic patients.5

      Another finding in the study by Meijer et alwas the relatively greater effect on bronchial hyperresponsiveness to adenosine monophosphate than to methacholine challenge with both oral and inhaled corticosteroid after two weeks. Similar findings have been reported after two weeks of treatment with inhaled budesonide powder in a dose of 1600 μg/ day.6 The authors not unreasonably suggested that adenosine monophosphate responsiveness might be more sensitive to changes in airway inflammation than methacholine. However, the treatment period was relatively short and one cannot exclude the possibility that the effects on methacholine hyperresponsiveness might have been proportionately greater with a longer duration of treatment, as has been reported in previous studies.7 8 It is also conceivable that differences in bronchial hyperresponsiveness between the doses of inhaled fluticasone may have become apparent with a longer duration of treatment.

      Finally, it is important not to extrapolate the results of the study by Meijer et al on patients with relatively mild asthma to more severe asthmatic patients in whom altered airway geometry may cause a reduction in lung delivery and lung bioavailability from narrowed peripheral small airways. Also, their results may be specific to the unique drug/device interaction of fluticasone propionate given via the dry powder inhaler, and further studies are needed to look at the dose-response relationship for the therapeutic ratio using more efficient delivery systems such as a pressurised metered dose inhaler with spacer.

      References

      authors' reply We thank Dr Lipworth for his interest in our article.1-1 Although we found no significant dose difference in PC20 adenosine monophosphate and methacholine or in sputum eosinophils over a two week period between the two doses of fluticasone, the trends suggested a favourable effect of 2000 μg compared with 500 μg per day for every parameter measured, and there was, indeed, a significant dose response effect on sputum levels of ECP. It is well known that the dose response curve for inhaled steroids in general is very shallow at conventional and higher doses, and we agree that from our data this seems to apply to fluticasone also. From our study, in which only two doses of fluticasone were used, we are careful not to overinterpret where the decline in the therapeutic ratio starts with this drug.

      We are aware that the respirable fraction of fluticasone in the dry powder formulation is lower than in the pressurised metered dose inhaler, although the suggested magnitude of the difference is debatable using data from Dr Lipworth's own group.1-2Unfortunately, in humans we still have considerable problems in separating the effects of common drugs on the large and the small airways, and the remarks by Dr Lipworth on the site of delivery are intuitively correct but, we believe, unproven as far as the clinical effects are concerned. There is no doubt that the dry powder formulation has systemic bioavailability and we clearly demonstrate this. We accept the notion that, with more sensitive markers of bioavailability, an effect might have been demonstrable also with the dose of 500 μg per day. The clinical relevance of this still needs to be determined even after so may years of using inhaled steroids.

      We agree that the improvement in hyperresponsiveness with steroid treatment can continue for much longer than the improvement in forced expiratory volume in one second (FEV1).1-3 The concept that the improvement in methacholine hyperresponsiveness might continue for a longer period than that of adenosine is interesting, but we are unaware of any data to substantiate this. In fact, in a study by Weersink and colleagues, the same difference between the two bronchoconstrictor agents held true for six weeks instead of the two weeks of fluticasone treatment in the current study.1-4

      It is interesting to debate whether the insufficient effect of inhaled steroids in patients with severe asthma is due to lower availability in the peripheral airways, as Dr Lipworth suggests, or, for instance, to a decreased sensitivity to steroids—either per se or as a result of increased inflammation and associated cytokine load.1-5 The suggestion by Dr Lipworth should result in a relatively better effect of systemic steroids compared with inhaled steroids, especially in the more obstructed patients, but this does not agree with our clinical impression. In fact, the finding of a superior effect of the inhaled corticosteroid over oral prednisolone (30 mg for two weeks) in our study rather suggests a contrary mechanism, perhaps compatible with a higher effectiveness of the lipophilic compound fluticasone at the level of the epithelium and (sub)mucosa than of systemic prednisolone, even if only in the larger airways. Nevertheless, we are careful not to extrapolate our findings beyond the devices and population studied. There are, however, in addition to ours, a few other studies which suggest that inhaled corticosteroids may have an effect at least as great as prednisolone in asthma exacerbations.1-6 1-7

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