A Dose-Range Comparison between Fluticasone Propionate and Budesonide, Measuring Their Effect on Bronchial Hyperresponsiveness and Adrenal Cortex Function |
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ABSTRACT |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Inhaled corticosteroids have become the mainstay treatment of bronchial asthma. However, simultaneous evaluations of efficacy and side effects are few. This study aimed to compare the relative effect of fluticasone propionate (FP) and budesonide (BUD) on bronchial responsiveness and endogenous cortisol secretion in adults with asthma. The study was double-blind and included 66 adults with asthma, who were randomized to FP (n = 33) or BUD (n = 33). Prestudy, all participants were clinically stable, using inhaled corticosteroids and hyperresponsive to methacholine. Eligible patients were randomized to three consecutive 2-wk periods with either FP 250 µg twice daily, FP 500 µg twice daily, and FP 1,000 µg twice daily, or BUD 400 µg twice daily, BUD 800 µg twice daily, and BUD 1,600 µg twice daily, delivered by Diskhaler and Turbuhaler, respectively. Before randomization and at the end of each treatment, bronchial methacholine PD20, 24-h urinary cortisol excretion (24-h UC), plasma cortisol, serum osteocalcin, and blood eosinophils were determined. The relative PD20 potency between FP and BUD was 2.51 (95% CI, 1.05-5.99; p < 0.05), while the relative 24-h UC potency was 0.60 (95% CI, 0.44-0.83; p < 0.01). The differential therapeutic ratio (FP/BUD) based on PD20 potency and 24-h UC was 4.18 (95% CI, 1.16-15.03; p < 0.05). The difference in systemic potency was also seen for plasma cortisol, serum osteocalcin, and blood eosinophils. Therapeutic ratio over a wide dose range, determined by impact on bronchial responsiveness and endogenous corticosteroid production, seems to favor FP.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
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Inhaled corticosteroids (ICS) have become established as first-choice drugs in the treatment of bronchial asthma (1,2). Their main advantage is high efficacy combined with few systemic side effects, when compared with previously used systemic steroids (3). A number of ICS have been introduced over the years, presenting different pharmacokinetics, pharmacodynamics, potency, and bioavailability, and more efficient delivery systems have been developed. Along with the increasing use of ICS by more patients and at higher dosages, this has emphasized the need to reconsider systemic side effects of ICS (4).
Numerous studies of different ICS have been performed; however, almost all have dealt with measurements either of potency or systemic effects (5). Only a few studies have attempted to examine efficacy and side effects concurrently, that is, have tried try to establish a therapeutic ratio. This must be considered as a key point, especially when comparing different ICS (6). Moreover, systemic effects on endogenous corticosteroid production are clearly dose related (7).
The present study was performed to provide a therapeutic ratio of two of the most widely used ICS, fluticasone propionate (FP) and budesonide (BUD), by comparing their impact on bronchial responsiveness and endogenous corticosteroid production, under clinically relevant conditions in adult patients with asthma.
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients
All patients had bronchial asthma according to guidelines (8, 9), that
is, had a history of episodic wheezing, cough and/or dyspnea, which
was reversible with bronchodilator treatment. The use of inhaled corticosteroids had reversed and stabilized the condition. At study entry,
all patients were clinically stable, that is, had FEV1 
60% of predicted, sparse symptoms during daytime, and no nightly awakenings.
No systemic corticosteroids were allowed for 2 mo before entry and
no upper respiratory tract infections within 6 wk. Patients with seasonal allergy were studied entirely outside season. At study entry patients had to receive inhaled corticosteroids, that is, fluticasone propionate (FP, 200-500 µg daily) or beclomethasone dipropionate (BDP)/
budesonide (BUD) (400-1,000 µg daily). The treatment had to be at a
fixed dose for at least 1 mo before entry. Furthermore, patients had to
demonstrate bronchial hyperresponsiveness, that is, 20% provocative
dose (PD20) 
800 µg methacholine bromide, on entry.
Design
This was a single-center, randomized, and double-blind study. It consisted of a baseline period of 2 to 4 wk, followed by three consecutive treatment periods of 2 wk each. During baseline, patients received 200 µg of BDP twice daily. Eligible patients were then randomized to treatment with either 250 µg of FP twice daily or 400 µg of BDP twice daily for 2 wk. During the second treatment period, patients received a double dose of the same medication, that is, 500 µg of FP twice daily or 800 µg of BUD twice daily, and in the last period doses were quadrupled, that is, 1,000 µg of FP twice daily or 1,600 µg of BUD twice daily. During the full study period, patients could use inhaled salbutamol (albuterol) as needed, apart from 4 h before study visits. BUD was given by Turbuhaler (Astra UK, London, UK), whereas remaining medications were delivered by Diskhaler (GlaxoWellcome, London, UK). Study medication was delivered by a double-dummy technique, that is, active medication was accompanied by Diskhaler or Turbuhaler placebo, as appropriate. The randomization sequence was generated by a computer at GlaxoWellcome. Study numbers were allocated in a consecutive order. The randomization code was held by GlaxoWellcome and was not available to the investigators until the study had been completed.
Patients were seen on study entry, at the time of randomization, and after each treatment period. Before randomization and by the end of each treatment, bronchial responsiveness to methacholine bromide, 24-h urine cortisol excretion (24-h UC), plasma cortisol, serum osteocalcin, and blood eosinophils were measured.
From study entry and onward, patients recorded daily morning
and evening peak expiratory flow (PEF), using a miniWright peakflow meter (Clement Clarke Ltd, Harlow, UK). Day and night symptoms were scored daily on scales ranging from 0 (no symptoms) to 5 (disabling symptoms) and from 0 (no symptoms) to 4 (symptoms
causing wakefulness all night), respectively. The daily use of rescue 
2-agonist was also recorded. These parameters were expressed as the
mean or median, as appropriate, of the 7 d preceding each visit.
Bronchial Methacholine Challenge
Bronchial methacholine challenge was done by means of dosimetry (Spira Elektro II; Respiratory Care Center, Hameenlinna, Finland). The dosimeter is an electrically valved system that enables automatic deliverance of a single nebulized dose during inhalation. This was performed according to a previously described method (10). Briefly, the dosimeter was adjusted to deliver a fixed amount of methacholine solution with each inhalation (nebulization time 0.5 s, start of nebulization at 50 ml, working pressure 2 atm). This allowed for calculation of the inhaled dose. The patient was then instructed in tidal breathing through a mouth piece (inspiratory flow ~ 0.5 L/s, inspiratory volume ~ 500-800 ml). Baseline FEV1 was determined 90 s after six inhalations of saline. The patient then inhaled from methacholine bromide solutions in cumulative dose steps starting with 18 µg, followed by 36, 72, 108, and 180 µg, and then doubling of doses eventually to 11,520 µg. FEV1 was measured 90 s after each inhalation step. Whenever FEV1 decreased 20% or more compared with baseline, the procedure was stopped and PD20 was calculated by interpolation of the cumulative dose (11).
Biochemistry
Twenty-four hour urine samples were collected on the last day of the run-in period and of each treatment period. The collection period went from 9:00 A.M. to 9:00 A.M. Blood samples were drawn at the same time of day at each occasion, preferentially between 8:00 A.M. and 10:00 A.M. Plasma and urine cortisol analyses were done with a commercially available fluoroimmunoassay (AutoDELFIA; Wallac Oy, Turku, Finland). The reference range of 24-h UC was 255-1306 nmol, whereas it was 244-727 nM for plasma cortisol. Twenty-four hour urine cortisol levels were corrected by creatinine excretion (Roche Diagnostics, Nutley, NJ).
Serum osteocalcin was analyzed by an in-house radioimmunoassay, using rabbit antiserum to bovine osteocalcin. The antiserum showed full cross-reactivity between human and bovine osteocalcin. The detection limit was 0.1 ng, with an intraassay coefficient of variance (CV) of 5% and a mean value of 9.1 ng/ml.
Blood eosinophils were determined by counting in a Fuchs-Rosenthal chamber. Briefly, peripheral blood was diluted (1:18) in a hypotonic solution containing acetone as stabilizer and eosin for staining of eosinophils. Between 20 min and 2 h later the number of eosinophils was counted in a Fuchs-Rosenthal chamber with a volume of 3.2 µl. All counts were performed in duplicate.
Analysis
Both the primary variables, PD20 and 24-h UC, were found to be normally distributed after logarithmic transformation and were therefore
transformed before all analyses. Geometric means and coefficients of
variation were calculated for these variables. Means and standard deviations were calculated for the nontransformed secondary variables,
that is, PEF, symptom scores, 2-agonist consumption, plasma cortisol, serum osteocalcin, and blood eosinophils.
Using baseline as covariate, the linearity and parallelism of the log dose-response curves of FP and BUD were tested separately for both PD20 and 24-h UC (Proc Mixed; SAS version 6.12 [Cary, NC]). For PD20 no evidence was found for lack of parallelism. Divergence from parallelism at higher doses was found for 24-h UC. No evidence was found for nonnormality in any model.
The relative potencies of FP and BUD together with their 95% confidence intervals were calculated separately for the two primary variables, using the horizontal differences between the two regression lines and the variance of their ratio in each case (12). Finally, the differential therapeutic ratio together with its 95% confidence interval was calculated as the ratio of the two relative potencies, again using the variance of the ratio.
The nontransformed secondary variables were analyzed as the change from baseline of each treatment period, using Student t test, testing the hypothesis of mean difference equal to zero.
All statistical analyses were based on the intent-to-treat population.
Ethics
The study conformed to the Declaration of Helsinki and to the guidelines of Good Clinical Practice. It was approved by the local scientific ethics committee (County of Aarhus) as well as the Danish National Board of Health. All patients gave informed consent in writing before entering the study.
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RESULTS |
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In total, 66 patients, aged 18-68 yr, were randomized to study treatment with either FP (n = 33) or BUD (n = 33). Baseline characteristics of the patients are listed in Tables 1 and 2. No significant differences were observed between treatment groups at baseline. Four patients withdrew during the study, one in the FP group (lost to follow-up) and three in the BUD group (noncompliance, lost to follow-up, and asthma exacerbation, respectively).
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Results of PD20 and 24-h UC measurements after the different study periods are seen in Table 2. The comparison of FP and BUD was as mentioned expressed as relative potency, that is, as the distance between the lines of linear regression of the dose response for each parameter and each treatment (Figure 1). The relative difference in impact on PD20 of FP and BUD (FP/BUD) was 2.51 (95% CI, 1.05-5.99; p < 0.05). Considering 24-h UC, the relative difference (FP/BUD) was 0.60 (95% CI, 0.44-0.83; p < 0.01). The relationship between treatment effects on bronchial hyperresponsiveness, that is, PD20, and endogenous corticosteroid metabolism, that is, 24-h UC, was estimated by a comparison of their relative potencies. This revealed a significant difference between FP and BUD of 4.18 (95% CI, 1.16-15.03; p < 0.05). Furthermore, BUD had a larger impact on plasma cortisol, serum osteocalcin, and blood eosinophils, when compared with FP (Figure 2).
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baseline) of (a) plasma cortisol, (b) serum osteocalcin,
and (c) blood eosinophils. Results are given as means ± SEM. Open columns, BUD; solid columns, FP, *p < 0.05, **p < 0.01, ***p < 0.001.
No significant differences were observed for either treatment, when considering PEF, symptom scores, and consumption of 2 agonist (Table 3). Adverse events were few, the
most frequent being headache and common cold. The occurrence was similar in the two treatment groups. No serious adverse events were seen in the study.
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DISCUSSION |
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This is the first study to present a combined evaluation of dose-response curves of efficacy and side effect parameters for two of the most commonly used ICS, that is, FP and BUD, in adults with asthma.
No single parameter is by itself sufficient to diagnose, classify severity of, or assess control of asthma. Bronchial hyperresponsiveness is a major characteristic of asthma, describing not only sensitivity to external stimuli but relating also to mucosal inflammation (13). A correlation between airway responsiveness to vasoactive amines and clinical end points has been demonstrated in several studies. Regarding corticosteroid treatment, airway responsiveness has been associated with other clinical end points, for example, severity of asthma (16), asthma symptoms, bronchodilator use, and exacerbations (17) as well as maximum bronchoconstrictory response (18). This has been substantiated by results from an interventional study in which additional monitoring of bronchial responsiveness to traditional monitoring parameters, that is, lung function and symptoms, provided an improved control in subjects with asthma over a 2-yr period (19).
The present study design and population were chosen, as we wanted to ascertain subjects to be steroid sensitive, that is, stabilized regarding lung function and symptoms after ICS treatment, but still allow for improvement of bronchial responsiveness. The efficacy of both FP and BUD on bronchial responsiveness to methacholine has been demonstrated in several studies (17, 20) with measureable results within 2 wk (21). It could be argued that 2 wk between dose increments was too short and could impose a risk of interference between time response and dose response. However, this seems of minor importance for several reasons. First, it seems reasonable to believe that evolvement of response over longer periods (months) would be equal for both corticosteroids studied. Second, most studies demonstrating increasing impact of inhaled corticosteroids on bronchial responsiveness over time have been performed in steroid-naive patients (18, 20). Finally, in one study (21), in which some patients were using inhaled corticosteroids before entry, bronchial hyperresponsiveness decreased slightly from 2 to 8 wk of treatment. However, no significant time effect was found in the analysis.
We were able to establish clear dose-response relationships for both study drugs, with respect to bronchial responsiveness. This is in accordance with previous data, although these are sparse and incomplete in subjects with asthma (21, 23, 24). More important, a significant relative difference of 2.5:1 in favor of FP was demonstrated. This is supported by a 2:1 ratio between FP and BUD, regarding other end points of efficacy (25). Moreover, indirect evidence is provided by a 1:1 ratio of beclomethasone dipropionate (BDP) and BUD, as well as a 1:2 ratio of BDP and FP, when considering impact on bronchial responsiveness (26, 27).
The changes in peak flows, symptom scores, and 2-agonist
consumption throughout the study were, as expected, very
small. This was, most likely, because study participants were
clinically stable on entry and, therefore, left little room for improvement of these parameters.
The results of the present study clearly demonstrated a difference in favor of FP, when regarding the primary parameter of systemic efficacy, that is, 24-h urinary cortisol excretion. 24-h UC is a well-recognized and sensitive parameter to reflect the systemic impact of ICS on the adrenal secretion of cortisol (4, 5). It could be argued that the 24-h UC dose-response curves are not parallel. However, the curves are diverging and the difference between the drugs tested increases proportionally with increasing doses. Thus, the relative difference actually seems underestimated, when considering higher and potentially more harmful dose levels.
Our results on 24-h UC contrast with several other studies, which have demonstrated ratios of FP to BUD ranging from 1 to 3.7 (28). Most were open studies performed in healthy individuals, applying relatively short treatment periods, ranging from 3.5 to 7 d (28, 31). However, healthy individuals are known to possess a higher degree of systemic absorption and, as a consequence, a greater impact of ICS on the hypothalamic-pituitary-adrenal (HPA) axis (7). Moreover, the time needed for exogenous corticosteroid to exert full suppressive efficacy on HPA axis, probably amounts to weeks or even months (7). In fact, this could to some extent be a criticism of the present design, which applied treatment periods of 2 wk.
Our results compared with the few studies of adults with asthma are also conflicting. However, one study was performed with single doses (29) whereas the other applied treatment periods of only 4 d (30) and participants had mild airway obstruction. Most important, neither study presented any kind of efficacy parameter for asthma. We aimed to study steroid-sensitive subjects with asthma of moderate severity, who by commonly used devices were given commonly used drugs in an appropriate dose range, and measure the pharmacological relationship between efficacy and side effects.
So far, only two studies have been published, presenting results on both efficacy and side effects of FP and BUD in adults with asthma (35, 36). These studies included 1,189 patients in all and demonstrated superior efficacy and lower systemic impact of FP compared with BUD at the double daily dose, during treatment periods of 6 and 12 wk, respectively. Although neither study attempted to establish dose-response relationships, the results support our findings.
Moreover, our data were supported by secondary parameters. Plasma cortisol fluctuates because of diurnal variations and, thus, is not considered an optimal marker of the HPA axis. However, it represents, along with markers of bone metabolism and inflammation, convincing evidence of the dose- response relationships seen for 24-h UC of FP and BUD.
In conclusion, the present study demonstrates different dose- response relationships of FP and BUD in adults with asthma over a wide dose range, when comparing their impact on bronchial responsiveness and endogenous corticosteroid production. The comparison reveals an approximate 4:1 ratio, but with quite a wide confidence interval. Nevertheless, this difference in parameters, in terms of bronchial reactivity and 24-h urinary cortisol excretion, seems to favor FP.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Lars Peter Nielsen, Department of Clinical Pharmacology, The Bartholin Building, University of Aarhus, 8000 Aarhus C, Denmark. E-mail: lpn{at}dadlnet.dk
(Received in original form December 15, 1999 and in revised form April 12, 2000).
Acknowledgments: The authors thank Associate Professor Niels Mygind for valuable help and comments. We appreciate the work of study nurse Dorte Kristensen, as well as that of laboratory technicians Anne Marie Toft and Birte Gahrn. We also thank Andreas Habicht and Chris Hallett of GlaxoWellcome for help on the statistical analysis.
Supported by GlaxoWellcome.
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References |
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REFERENCES
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M. J. TOBIN Asthma, Airway Biology, and Allergic Rhinitis in AJRCCM 2000 Am. J. Respir. Crit. Care Med., November 1, 2001; 164(9): 1559 - 1580. [Full Text] [PDF]
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P.M. Meek, S.C. Lareau, and D. Anderson Memory for symptoms in COPD patients: how accurate are their reports? Eur. Respir. J., September 1, 2001; 18(3): 474 - 481. [Abstract] [Full Text] [PDF]
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B. J. Lipworth, S. Edsbacker, L. P. Nielsen, and R. Dahl THE PROBLEM OF DOSE-RESPONSE AND THERAPEUTIC RATIO OF INHALED STEROIDS Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1758 - 1759. [Full Text] [PDF]
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