Chest -- eLetters for Weiner et al., 116 (4) 931-934

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ASTHMA:
Paltiel Weiner, Noa Berar-Yanay, Avi Davidovich, and Rasmi Magadle
Nocturnal Cortisol Secretion in Asthmatic Patients After Inhalation of Fluticasone Propionate
Chest 1999; 116: 931-934 [Abstract] [Full text] [PDF]

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HPA-AXIS SUPPRESSION WITH INHALED FLUTICASONE: Brian J Lipworth (11 November 1999)

HPA-AXIS SUPPRESSION WITH INHALED FLUTICASONE 11 November 1999

Brian J Lipworth,
Professor of Allergy and Respiratory Medicine
University of Dundee, Asthma and Allergy Research Group, Ninewells Hospital and Medical School
Send letter to journal:
Re: HPA-AXIS SUPPRESSION WITH INHALED FLUTICASONE

b.j.lipworth{at}dundee.ac.uk Brian J Lipworth

The study of Weiner and colleagues shows a strong correlation between the degree of adrenal suppression with fluticasone and airway calibre in terms of percent predicted FEV1. Hence, as the authors correctly point out the absolute magnitude of adrenal suppression will depend on the severity of asthmatics who are studied. Nonetheless, it is still valid to either compare two different drugs or to compare two different formulations of the same drug using healthy volunteers, where the ratio for the difference is likely to be the same, although the absolute magnitude of response will be greater in healthy compared to asthmatic subjects. There are indeed good data from the literature to substantiate this statement. for example, when comparing budesonide and fluticasone propionate given via metered dose inhalers in dose-response studies, relative potency ratios between the two drugs for suppression of 8 am plasma cortisol where 3.5 in asthmatic subjects compared to 3.1 in healthy subjects(1,2). In another two dose-response studies comparing budesonide and fluticasone propionate given via their respective dry powder inhalers, the potency ratios for suppression of area under curve for plasma cortisol were 2.1 in asthmatic subjects compared to 1.7 in healthy volunteers(3,4). However, it is reassuring from the data of Weiner et al that patients with more severe airflow obstruction (who require higher doses of inhaled steroid) will be relatively protected from systemic adverse effects of potent inhaled corticosteroids due to a reduction in lung bioavailability.
The findings of Weiner et al may have underestimated the degree of adrenal suppression in response to a single 500痢 dose of fluticasone dry powder inhaler. Since fluticasone has a half-life of 14.5 hours which is longer than the 12 hour dosing interval, this will result in drug accumulation at steady-state, and hence an increase in adrenal suppression seen with repeated twice daily dosing(5,6). Furthermore, in vitro studies have shown that the fluticasone Diskhaler dry powder device delivers a two -fold lower respirable fine particle dose compared to fluticasone propionate pressurised metered dose inhaler(7). The lower respirable fine particle dose from the fluticasone dry powder inhaler will also result in reduced lung bioavailability, as shown in a study where there was a five- fold less adrenal suppression compared to the same nominal dose of fluticasone delivered via a pressurised metered dose inhaler with spacer device(8). Thus, it is likely that even in patients with more severe airflow obstruction, using fluticasone propionate via a spacer device with repeated dosing would result in a greater degree of adrenal suppression than was observed in the study of Weiner et al using a single dose from a dry powder device. The more central airway deposition associated with the larger particle size from the fluticasone Diskhaler would also be associated with a commensurate reduction in anti-asthmatic efficacy as a consequence of the attenuated fine particle dose delivery to the smaller airways.
The systemic adverse effects of higher potency inhaled corticosteroids such as fluticasone should not be taken lightly, even in more severe patients in whom it maybe possible to wean off their oral prednisone. For example, in a recent dose-ranging study in asthmatic patients with impaired small airway function (mean FEF25-75 65.5% predicted), it was found that the relative dose ratio for relative potency was 8.5:1mg (95% CI 5.7 to 11.2) when comparing oral prednisone with inhaled fluticasone given via a spacer, for suppression of 8 am plasma cortisol(9). This is supported by a meta-analysis from 13 studies which evaluated effects on 8 am plasma cortisol, where oral prednisolone and inhaled fluticasone exhibited a 10:1mg equivalence(10).
For practical purposes it is clearly not feasible to use repeated hourly measurements of overnight plasma cortisol for routine outpatient screening. The use of 24 hour and fractionated (daytime, nighttime and early morning) serum cortisol and urinary cortisol/creatinine was investigated in asthmatic patients receiving inhaled fluticasone or triamcinolone acetonide, showing that the use of overnight urinary cortisol/creatinine exhibited the largest signal to noise ratio in terms of the mean difference and intra-individual variability, as compared to integrated 24 hour serum or urine measurements(11) .
All of these finding emphasise the importance of always trying to step-down to achieve the lowest maintenance dose of inhaled corticosteroid therapy for a given drug-device combination, as this will minimise the long-term potential burden for systemic adverse effects.
Dr Brian Lipworth, MD, FRCPE Professor of Allergy and Respiratory Medicine
References
1. Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997; 52: 55-58.
2. Donnelly AR, Glass M, Minkwitz MC, Casale TM. The leukotriene D4 receptor antagonists, ICI204219, relieve symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med 1995; 151: 1734-1739.
3. Grahnen A, Jansson B, Brunden RM, Ling-Andersson A, Lonnebo A, Johansson M, Eckernas SA. A dose-response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbuhaler. Eur J Clin Pharmacol 1997; 52: 261-267.
4. Derom E, Van Schoor J, Verhaeghe W, Vincken W, Pauwels R. Systemic effects of inhaled fluticasone propionate and budesonide in adult patients with asthma. Am J Respir Crit Care Med 1999; 168: 157- 161.
5. Thorsson L, Dahlstrom K, Edsbacker S, Kallen A, Paulson J, Wiren JE. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997; 43: 155-161.
6. Lonnebo A, Grahnen A, Jansson B, Brunden RM, Ling-Andersson A. An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate, in inhaled budesonide in healthy volunteers. Eur J Clin Pharmacol 1996; 49: 459-463.
7. Olsson B. Aerosol particle generation from dry-powder inhalers - can they equal pressurized metered dose inhalers? J Aerosol Med 1995; 8(3): S13-S19.
8. Wilson AM, Dempsey OJ, Coutie WJR, Sims EJ, Lipworth BJ. Importance of drug device interaction in determining systemic effects of inhaled corticosteroids. Lancet 1999; 353: 2128.
9. Wilson AM, Lipworth BJ. Short term dose-response relationships for the relative systemic effects of oral prednisolone and inhaled fluticasone and in asthmatic adults. Br J Clin Pharmacol 1999; 48: 579-585.
10.Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: 941-955.
11.Wilson AM, Lipworth BJ. 24 hour and fractionated profiles of adrenocortical activity in asthmatic patients receiving inhaled and intranasal corticosteroids. Thorax 1999; 54: 20-26.