THE PROBLEM OF DOSE-RESPONSE AND THERAPEUTIC RATIO OF INHALED STEROIDS

To the Editor :

I read with interest the article by Nielsen and Dahl comparing the therapeutic ratio of dry powder inhaled (DPI) fluticasone propionate and budesonide (1). The study involved giving patients with mild to moderate asthma up to 3200 µg daily of budesonidetwice the maximal recommended dose for severe persistent asthma. Each dose was administered for two weeks, and if a longer period had been given, the steep part of the dose-response curve for bronchial hyperresponsiveness would have been seen at much lower doses. Furthermore, the actual slope might have been steeper with longer treatment, which would alter the potency ratio.

Baseline PD₂₀ with budesonide (259 µg) and fluticasone (271 µg), would indicate a mild degree of hyperresponsiveness and, consequently, little room for improvement. This is highlighted by only a 0.11 doubling dose improvement between baseline versus budesonide 800 µg and 0.38 doubling doses versus budesonide 1600 µg. To put this into perspective, in a previous study of mild to moderate asthmatics, methacholine PD₂₀ was measured at baseline (PD₂₀ = 18 µg), with a subsequent 1.7 doubling dose shift after budesonide 800 µg for 3 weeks and 2.7 doubling doses after 1600 µg for 3 weeks (2). This suggests that their potency ratio was probably influenced by the rather shallow slope of the dose-response curve with both drugs.

One would have predicted that the relative potency between fluticasone and budesonide DPI would be closer to unity since the twofold difference in glucocorticoid potency between fluticasone and budesonide is likely to be offset by the twofold greater respirable dose between the DPI's (3). For example, in asthmatic children receiving budesonide and fluticasone DPI, there was no difference in the lowest effective maintenance dose or in urinary cortisol excretion (4).

The slopes for suppression of 24-h uncorrected urinary cortisol were markedly different, and so it is not possible to make a proper estimate of relative potency. Also, one would have to cast doubt on the validity of the uncorrected urinary cortisol data, as it is more conventional to correct for urinary creatinine excretion. The findings of Nielsen and Dahl for cortisol suppression are not consistent with other data from asthmatic patients, were steady-state dosing with fluticasone 2000 µg daily and budesonide 1600 µg daily produced 34% versus 16% suppression of the 20-h area under curve plasma cortisol profile (5). Finally, in a meta-analysis of 21 studies evaluating urinary cortisol, the slope for fluticasone was 4.3-fold (p < 0.001) steeper than for budesonide (6).

Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland

1. Nielsen LP, Dahl R. Therapeutic ratio of inhaled corticosteroids in adult asthma: a dose- range comparison between fluticasone propionate and budesonide, measuring their effect on bronchial hyperresponsiveness and adrenal cortex function. Am J Respir Crit Care Med 2000; 162: 2053-2057 [Abstract/Free Full Text].

2. Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild to moderate asthma. Am J Med 2000; 108: 269-275 [Medline].

3. Olsson B. Aerosol particle generation from dry-powder inhalers: can they equal pressurized metered dose inhalers? J Aerosol Med 1995; 8: S13-S19 .

4. Agertoft L, Pedersen S. A randomized, double-blind dose reduction study to compare the minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler. J Allergy Clin Immunol 1997; 99: 773-780 [Medline].

5. Derom E, Van Schoor J, Verhaeghe W, Vinken W, Pauwels R. Systemic effects of inhaled fluticasone propionate and budesonide in adult patients with asthma. Am J Respir Crit Care Med 1999; 160: 157-161 [Abstract/Free Full Text].

6. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: 941-955 [Abstract/Free Full Text].

To the Editor :

The article by Nielsen and Dahl (1) concludes that fluticasone has a higher therapeutic ratio than budesonide. On the basis of the data presented, this conclusion appears unlikely.

As an efficacy measure, bronchial hyperresponsiveness was used, which is less suitable because of its marked time-dependency. Full effects of inhaled steroids are not reached within two weeks as used by the authors, rather several months are needed (2). In addition, the rate of improvement may differ between different doses (3) and by that also between different steroids. Such factors make the design selected by Nielsen and Dahl unsuitable for potency comparisons.

Furthermore, using cumulative dose response, comparing doses that are not equal on a microgram-to-microgram basis creates a bias in favor of the lower doses. An initial low dose may result in substantial improvement, whereas subsequent higher doses result in relatively small further improvements. This underscores the need to work on the same part of the dose- response curve for the two drugs.

In regard to the systemic effects, Nielsen and Dahl claim lower cortisol suppression with fluticasone. The authors acknowledge that their finding is in contrast to several other studies, and this could have been further substantiated by the inclusion of a systematic review and meta-analysis from 1999 comprising 21 dose-response studies on inhaled steroids using urinary cortisol as measure. This analysis consistently showed less cortisol suppression for budesonide than for fluticasone (4).

The explanations provided by the authors for their divergent results on cortisol suppression are that most of the other studies were performed in healthy volunteers and were of short duration, from 3.5-7 d. However, the majority of cortisol assessment studies have been performed in asthmatic patients (4). The suggestion that time may change the relation in regards to cortisol suppression between the two drugs implies that this shift should have taken place during the second week of their study. Nielsen and Dahl provide no data to support this hypothesis, which overall seems highly unlikely, especially as the patients were treated with inhaled steroids for at least one month before entering the study, according to the inclusion criteria.

Careful down-titration of doses, measurement of lung function, and recording of asthma symptoms, show that budesonide via Turbuhaler and fluticasone via Diskhaler are clinically equipotent (5). On the systemic side, fluticasone exerts a higher cortisol suppression than any other inhaled corticosteroid (4), which most probably is explained by the marked systemic accumulation of the drug (5).

AstraZeneca Research and Development, Lund, Sweden

1. Nielsen LP, Dahl R. Therapeutic ratio of inhaled corticosteroids in adult asthma. Am J Respir Crit Care Med 2000; 162: 2053-2057 .

2. Fuller RW, Choudry NB, Eriksson G. Action of budesonide on asthmatic bronchial hyperresponsiveness: effects on directly and indirectly acting bronchoconstrictors. Chest 1991; 100: 670-674 [Abstract/Free Full Text].

3. Reddel HK, Jenkins CR, Marks GB, Ware SI, Xuan W, Salome CM, Badcock GA, Woolcock AJ. Optimal asthma control, starting with high doses of inhaled budesonide. Eur Respir J 2000; 16: 226-235 [Abstract].

4. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: 941-955 .

5. Agertoft L, Pedersen S. A randomized, double-blind dose reduction study to compare the minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler. J Allergy Clin Immunol 1997; 99: 773-780 .

6. Thorsson L, Dahlström K, Edsbäcker S, Källen A, Paulson J, Wiren JE. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997; 43: 155-161 [Medline].

From the Authors :

We thank Drs. Edsbäcker and Lipworth for their interest in our article (1). We note with interest that the authors do not offer any major new criticism of our study that we had not already considered and self-critiqued in the discussion of our article (including the duration of treatment and the applicability of the outcome measures chosen). We appreciate that our data are inconsistent with the proportion of the literature to which Drs. Edsbäcker and Lipworth both refer and, indeed, we discussed many of the original articles that contributed to the meta-analysis that they mention (2) in our discussion. The studies that show fluticasone propionate to have a greater effect on cortisol levels than budesonide are those conducted in healthy volunteers or in patients with very mild asthma receiving high corticosteroid doses. Moreover, the meta-analysis (2), treatment with fluticasone propionate in adult asthmatics was considered in only five of 21 studies, including 56 individuals in all. This seems a quite fragile basis for the categorical statement on comparative bioavailability made by Dr. Edsbäcker. It is now well-established that the systemic bioavailability of fluticasone propionate is at least 2-fold higher in healthy volunteers than in patients with asthma of the appropriate severity for the dose (3). Indeed, the results of our double-blind, placebo-controlled study are entirely consistent with the remainder of the literature that Drs. Edsbäcker and Lipworth do not mention, in which fluticasone propionate and budesonide are given to patients with asthma at therapeutically appropriate doses (see 6 for meta-analysis).

LARS PETER NIELSEN

RONALD DAHL

Aarhus University Hospital

Aarhus, Denmark

1. Nielsen LF, Dahl R. Therapeutic ratio of inhaled corticosteroids in adult asthma: a dose-range comparison between fluticasone propionate and budesonide, measuring their effect on bronchial hyperresponsiveness and adrenal cortex function. Am J Respir Crit Care Med 2000; 162: 2053-2057 .

2. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: 941-955 .

3. Brutsche MH, Brutsche IC, Munavvar M, Langley SJ, Masterson CM, Daley-Yates PT, Brown R, Custovic A, Woodcock A. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000; 356: 556-561 [Medline].

4. Daley-Yates PT, Tournant J, Kunka RL. Comparison of the systemic availability of fluticasone propionate in healthy volunteers and patients with asthma. Clin Pharmacokinet 2000;399(Suppl):39-45.

5. Harrison TW, Wisniewski A, Honour JW, Tattersfield AE. Systemic activity of inhaled fluticasone propionate and budesonide in patients with and without asthma. Eur Respir J 1999;14(Suppl 30)446s.

6. Barnes NC, Hallett C, Harris TAJ. Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less. Respir Med 1998; 92: 95-104 [Medline].