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Fluticasone propionate bioavailability in asthma
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE Fluticasone propionate bioavailability in asthma Sir—Martin Brutsche and colleagues (Aug 12, p 556)1 conclude that inhaled corticosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for disease severity and not in normal volunteers. We believe however that there are flaws in this argument. Comparison of the plasma areaunder-curve concentration for fluticasone propionate over 12 h after inhalation shows a highly significant difference (62%) between the asthmatic and control group, whereas the plasma cortisol concentrations do not differ significantly (20%) over 12 h. The discrepancy between the large difference in plasma fluticasone propionate concentration but not in plasma cortisol concentration after inhalation in patients with asthma compared with controls can be explained by the partitioning of fluticasone propionate between plasma and systemic tissue compartments. Fluticasone propionate has a large volume of distribution estimated at 859 L,2 and, consequently, only a small fraction of the amount of drug in the body will be found in the plasma. Consequently, measuring the plasma concentration of fluticasone in the water soluble plasma compartment will underestimate the total systemic body exposure. An analogy is a wet sponge, from which the constant drip represents the plasma compartment, and the total body exposure as the water that comes out when the sponge is squeezed. To assess the absolute degree of adrenal suppression of inhaled fluticasone, we agree that studies should be done in asthmatic patients. To assess the relative degree of adrenal suppression, such as for two different inhaled corticosteroids, study of healthy volunteers is probably still valid. For example, fluticasone propionate and budesonide given via metered-dose inhalers give a relative potency ratio for suppression of 0800 h serum cortisol of 3·1 in healthy volunteers and 3·5 in patients with asthma.3,4 Other published data do not, however, support differences in absolute cortisol suppression between asthmatic and healthy subjects. Steadystate administration of 2000 g fluticasone propionate per day via
THE LANCET • Vol 356 • November 11, 2000
metered dose inhaler can suppress overnight urinary cortisol in patients with asthma by 60% compared with 53% in healthy volunteers, whereas 1600 g with spacer triamcinolone acetonide per day (ex-actuator dose) suppresses overnight urinary cortisol by 30% in patients with asthma and healthy volunteers. Study of healthy volunteers also obviates potential differences in baseline cortisol concentrations, as was seen by Brutsche and colleagues, and pre-existing inhaled corticosterioid treatment in patients with asthma leads to striking down-regulation of peripheral glucocorticoid receptors. Brutsche and colleagues studied fluticasone delivered via a spacer device, which delivers a much higher fine-particle dose than fluticasone dry powder inhaler. Thus, their results might be peculiar to the spacer device, since the coarser particles delivered from the dry-powder inhaler could lead to a less pronounced difference between healthy volunteers and patients with asthma, because of a more proximal deposition pattern. For example, in healthy volunteers in whom fluticasone propionate via a spacer device was compared with a drypowder inhaler, there was a five-fold difference in adrenal suppression between the two devices.5 Finally, a meta-analysis of 21 studies that assessed dose-response effects of inhaled corticosteroids on suppression of urinary cortisol (mostly from asthmatic patients), fluticasone propionate exhibited a significantly greater slope gradient than beclometasone dipropionate (1·9-fold, p<0·05), triamcinolone acetonide (3·7fold, p<0·05), or budesonide (4·3-fold, p<0·001). *Brian J Lipworth, Stephen Fowler, Andrew Wilson Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK (e-mail: [email protected]) 1
Brutsche MH, Brutsche IC, Munawar M, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000; 356: 556–61.
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3
4
5
Thorsson L, Dahlstrom K, Edsbacker S, et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997; 43: 155–61. Donnelly R, Williams KM, Baker B, et al. Effects of budesonide and fluticasone on 24 hour plasma cortisol: a dose response study. Am J Respir Crit Care Med 1997; 156: 1746–51. Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997; 52: 55–58. Wilson AM, Dempsey AM, Coutie WJR, et al. Importance of drug device interaction in determining systemic effects of inhaled corticosteroids. Lancet 1999; 353: 2128.
Sir—Martin Brutsche and colleagues1 lead us to believe that propionate pharmacokinetics and systemic effects are studied in 11 healthy volunteers. There must, however, be substantial doubt about the diagnosis of asthma in the patients included. The criteria Brutsche and colleagues use to establish a diagnosis of asthma are a physician’s diagnosis of asthma, a forced expiratory volume in 1 s (FEV1) of less than 75% predicted normal, previous bronchodilator use, and a stable condition on high-dose inhaled corticosteroids. Also participants were eligible provided that they had not smoked for at least 6 months. These so-called asthmatics had a mean FEV1 of 54% predicted normal and a residual volume of 161% predicted. I suggest that if these patients had ever had asthma they had fixed airflow obstruction at the time of the investigation, and that this diagnosis should have replaced asthma in the title. I remind Brutsche and colleagues that one important aim of asthma treatment is to restore normal or best possible long-term airway function,2 and that restoration of normal or nearnormal lung function is possible in most patients with asthma, although possibly not in patients with chronic airways disease referred to specialist hospital centres. As Elliot Israel indicates in his commentary (Aug 12, p 527)3 on Brutsche and colleagues’ report, the important unanswered question is what are the consequences of response to inhaled steroid therapy? I suggest that in asthmatics responding
1681
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
CORRESPONDENCE Fluticasone propionate bioavailability in asthma Sir—Martin Brutsche and colleagues (Aug 12, p 556)1 conclude that inhaled corticosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for disease severity and not in normal volunteers. We believe however that there are flaws in this argument. Comparison of the plasma areaunder-curve concentration for fluticasone propionate over 12 h after inhalation shows a highly significant difference (62%) between the asthmatic and control group, whereas the plasma cortisol concentrations do not differ significantly (20%) over 12 h. The discrepancy between the large difference in plasma fluticasone propionate concentration but not in plasma cortisol concentration after inhalation in patients with asthma compared with controls can be explained by the partitioning of fluticasone propionate between plasma and systemic tissue compartments. Fluticasone propionate has a large volume of distribution estimated at 859 L,2 and, consequently, only a small fraction of the amount of drug in the body will be found in the plasma. Consequently, measuring the plasma concentration of fluticasone in the water soluble plasma compartment will underestimate the total systemic body exposure. An analogy is a wet sponge, from which the constant drip represents the plasma compartment, and the total body exposure as the water that comes out when the sponge is squeezed. To assess the absolute degree of adrenal suppression of inhaled fluticasone, we agree that studies should be done in asthmatic patients. To assess the relative degree of adrenal suppression, such as for two different inhaled corticosteroids, study of healthy volunteers is probably still valid. For example, fluticasone propionate and budesonide given via metered-dose inhalers give a relative potency ratio for suppression of 0800 h serum cortisol of 3·1 in healthy volunteers and 3·5 in patients with asthma.3,4 Other published data do not, however, support differences in absolute cortisol suppression between asthmatic and healthy subjects. Steadystate administration of 2000 g fluticasone propionate per day via
THE LANCET • Vol 356 • November 11, 2000
metered dose inhaler can suppress overnight urinary cortisol in patients with asthma by 60% compared with 53% in healthy volunteers, whereas 1600 g with spacer triamcinolone acetonide per day (ex-actuator dose) suppresses overnight urinary cortisol by 30% in patients with asthma and healthy volunteers. Study of healthy volunteers also obviates potential differences in baseline cortisol concentrations, as was seen by Brutsche and colleagues, and pre-existing inhaled corticosterioid treatment in patients with asthma leads to striking down-regulation of peripheral glucocorticoid receptors. Brutsche and colleagues studied fluticasone delivered via a spacer device, which delivers a much higher fine-particle dose than fluticasone dry powder inhaler. Thus, their results might be peculiar to the spacer device, since the coarser particles delivered from the dry-powder inhaler could lead to a less pronounced difference between healthy volunteers and patients with asthma, because of a more proximal deposition pattern. For example, in healthy volunteers in whom fluticasone propionate via a spacer device was compared with a drypowder inhaler, there was a five-fold difference in adrenal suppression between the two devices.5 Finally, a meta-analysis of 21 studies that assessed dose-response effects of inhaled corticosteroids on suppression of urinary cortisol (mostly from asthmatic patients), fluticasone propionate exhibited a significantly greater slope gradient than beclometasone dipropionate (1·9-fold, p<0·05), triamcinolone acetonide (3·7fold, p<0·05), or budesonide (4·3-fold, p<0·001). *Brian J Lipworth, Stephen Fowler, Andrew Wilson Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK (e-mail: [email protected]) 1
Brutsche MH, Brutsche IC, Munawar M, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000; 356: 556–61.
2
3
4
5
Thorsson L, Dahlstrom K, Edsbacker S, et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997; 43: 155–61. Donnelly R, Williams KM, Baker B, et al. Effects of budesonide and fluticasone on 24 hour plasma cortisol: a dose response study. Am J Respir Crit Care Med 1997; 156: 1746–51. Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997; 52: 55–58. Wilson AM, Dempsey AM, Coutie WJR, et al. Importance of drug device interaction in determining systemic effects of inhaled corticosteroids. Lancet 1999; 353: 2128.
Sir—Martin Brutsche and colleagues1 lead us to believe that propionate pharmacokinetics and systemic effects are studied in 11 healthy volunteers. There must, however, be substantial doubt about the diagnosis of asthma in the patients included. The criteria Brutsche and colleagues use to establish a diagnosis of asthma are a physician’s diagnosis of asthma, a forced expiratory volume in 1 s (FEV1) of less than 75% predicted normal, previous bronchodilator use, and a stable condition on high-dose inhaled corticosteroids. Also participants were eligible provided that they had not smoked for at least 6 months. These so-called asthmatics had a mean FEV1 of 54% predicted normal and a residual volume of 161% predicted. I suggest that if these patients had ever had asthma they had fixed airflow obstruction at the time of the investigation, and that this diagnosis should have replaced asthma in the title. I remind Brutsche and colleagues that one important aim of asthma treatment is to restore normal or best possible long-term airway function,2 and that restoration of normal or nearnormal lung function is possible in most patients with asthma, although possibly not in patients with chronic airways disease referred to specialist hospital centres. As Elliot Israel indicates in his commentary (Aug 12, p 527)3 on Brutsche and colleagues’ report, the important unanswered question is what are the consequences of response to inhaled steroid therapy? I suggest that in asthmatics responding
1681
For personal use only. Not to be reproduced without permission of The Lancet.