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(Chest. 1999;116:935-940.)
© 1999 American College of Chest Physicians

Evaluation of the Effect of a Large Volume Spacer on the Systemic Bioactivity of Fluticasone Propionate Metered-Dose Inhaler*

Owen J. Dempsey, MD; Andrew M. Wilson, MD; Wendy J. R. Coutie, HNC and Brian J. Lipworth, MD

* From the Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Scotland, UK.

Correspondence to: Brian J. Lipworth, MD, Professor of Allergy & Respiratory Medicine, Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital & Medical School, Dundee, Scotland, UK; e-mail: b.j.lipworth{at}dundee.ac.uk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Inhaled corticosteroids such as fluticasone propionate (FP) have dose-related systemic effects, including adrenal suppression. We have therefore investigated the effect of adding a large volume spacer on the systemic bioactivity of FP given via a pressurized metered-dose inhaler (pMDI).

Methods: Fourteen healthy volunteers (mean age, 29.9 years old) were studied using an open, randomized, placebo-controlled, three-way crossover design. Single doses of the following were given at 5:00 PM in a randomized sequence: (1) eight puffs of FP by pMDI, 1.76 mg (250 µg ex-valve, 220 µg ex-actuator); (2) eight puffs of FP by pMDI, 250 µg, with 750-mL spacer (Volumatic; Allen & Hanburys; Uxbridge, UK); and (3) eight puffs of placebo by pMDI. Measurements were made after each dose, including overnight and early morning urinary cortisol/creatinine ratios and 8:00 AM serum cortisol.

Results: Significant (p < 0.05) suppression of all three end points occurred with each active treatment compared to treatment with placebo. Furthermore, significant (p < 0.05) additional suppression occurred when comparing FP by pMDI alone to FP by pMDI with spacer. Geometric mean fold differences (95% confidence interval for fold difference) between FP by pMDI alone and FP by pMDI with spacer were 1.94-fold (1.00–3.78) for overnight urinary cortisol/creatinine ratio and 1.98-fold (1.26–3.10) for 8:00 AM serum cortisol. This was mirrored by a twofold rise in the number of values for uncorrected overnight urinary cortisol < 10 nmol/10 h: placebo treatment (none of 14 subjects); FP by pMDI (6 of 14 subjects; 43%); and FP by pMDI with spacer (12 of 14 subjects; 86%).

Conclusions: The use of a large volume spacer with FP by pMDI results in a twofold increase in the systemic bioavailability as assessed by sensitive measures of adrenal suppression. This, in turn, reflects a twofold improvement in respirable dose delivery with the spacer device.

Key Words: adrenal suppression • asthma • fluticasone propionate • inhaled corticosteroids • spacer


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled corticosteroids are currently recognized as the first-line anti-inflammatory therapy in patients with asthma.1 It is recognized, however, that all inhaled corticosteroids are associated with dose-related systemic adverse effects that occur secondary to absorption into the systemic circulation via the GI tract or the lung.2

Many patients receive inhaled corticosteroids via pressurized metered-dose inhalers (pMDIs), often in conjunction with a spacer device, as advocated in current United States guidelines.1 These devices work by reducing aerosol velocity and droplet size, thus reducing the number of large particles impacting in the mouth.3 Furthermore, the use of a spacer increases the respirable dose of fine particles (ie, aerodynamic mean mass diameter of < 5 µm) reaching the bronchial tree.4

What potential advantages are conferred by combining a pMDI with a spacer? Firstly, there is a reduction in local complications such as oral candidiasis and dysphonia, particularly with higher doses of corticosteroid.5 Secondly, many patients using pMDIs have a poor inhaler technique that can be obviated by using a spacer.6 Thirdly, increased intrapulmonary deposition of corticosteroid increases clinical efficacy for a given nominal dose.5 In view of markedly reduced oropharyngeal deposition and, therefore, reduced oral bioavailability, there is data to suggest that a spacer may help reduce systemic adverse effects.7 8 9 10 11

However, this last point may not apply equally to all inhaled corticosteroids as a consequence of their differing degrees of hepatic first-pass metabolism.12 For example, beclomethasone dipropionate has approximately 60 to 70% hepatic first-pass inactivation of the swallowed fraction,13 and hence a spacer would be expected to reduce overall systemic bioavailability, due to decreased oral bioavailability outweighing any increase in lung bioavailability. In view of the negligible oral bioavailability of fluticasone propionate (FP) as a result of almost complete first-pass hepatic metabolism of the swallowed fraction,14 15 we therefore hypothesized that spacer use, by increasing the respirable dose, would be expected to increase its systemic bioactivity, as opposed to a pMDI alone.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Fourteen healthy nonsmoking volunteers were recruited into the study. Their mean age (SEM) was 29.9 years old (2.5) and mean percent predicted FEV1 (SEM) was 106% (2.4). The patients were all nonsmokers with no history of respiratory or other disease. In addition, all had normal findings on physical examination, spirometry, urinalysis, and routine hematology/biochemical blood tests. Pregnant women and those taking the oral contraceptive pill were excluded. Approval for the study was obtained from the Tayside Medical Ethics Committee, and all patients gave written informed consent.

Study Design
This was an open-label, single-center, placebo-controlled, randomized study with a three-way crossover design. The subjects attended an initial screening during which they were instructed in the correct use of a pMDI by using an aerosol inhalation monitor device (Vitalograph; Bucks, UK). The correct inhaler technique was also reinforced at each subsequent laboratory visit.

There were three separate laboratory visits, each separated by at least a 5-day washout period. All treatments were administered under supervision at the same time of day (5:00 PM), without mouth rinsing or gargling. All of the pMDIs were "primed" prior to use by discharging six puffs, and they were shaken vigorously immediately before actuation.

The treatment options, given in randomized sequence, were as follows: (1) eight consecutive puffs of placebo by pMDI; (2) eight consecutive puffs of FP by pMDI (Flixotide; Allen & Hanburys; Uxbridge, UK), 250 µg ex-valve per actuation, 220 µg ex-actuator (total dose ex-valve 2 mg, total dose ex-actuator 1.76 mg); (3) eight consecutive puffs of FP by pMDI used in conjunction with a primed 750 mL large volume plastic spacer device (Volumatic; Allen & Hanburys). The dose used is within the daily dosage range of up to 1.76 mg/d as recommended by the manufacturer. This dose was chosen not to represent a common clinically used dose, but rather to ensure a detectable systemic signal in terms of adrenal suppression, with the aim of detecting differences between the two devices.

Each spacer had previously been washed in detergent and drip dried, followed by priming with five puffs of FP, in order to reduce electrostatic charge and to optimize respirable dose delivery. The package insert instructions were followed: after exhaling to residual volume, the subject actuated the inhaler once and immediately inspired steadily and deeply to total lung capacity, and this was followed by breath holding for 10 s. Following this, the subject breathed into the spacer again and repeated the inspiratory maneuver, and this was followed by breath holding for 10 s. This procedure was repeated for each of the remaining doses, eight actuations in total, and each subject used the same spacer throughout the study.

Measurements
After the completion of the inhalation sequence, the subjects went home with written instructions to collect an overnight urinary cortisol sample at 10:00 PM. All of the subjects were asked to retire to bed before midnight. The subjects were asked to empty their bladder at 10:00 PM and to collect all of the voided urine until they returned to the laboratory the next day at 7:30 AM. They were asked to lie supine for 30 min before taking an 8:00 AM plasma cortisol sample. Following this, subjects voided another sample of urine at 8:00 AM to complete the 10-h collection. The volume of the total sample was recorded, and aliquots were taken for urinary cortisol and creatinine for overnight (10 h) and early morning (8:00 AM) measurements.

Assays
All assays were performed in duplicate in a blinded fashion by a separate technician. Serum cortisol was measured with a commercial radioimmunoassay kit (Incstar Ltd.; Wokingham; Berkshire, UK) that has no crossreactivity with FP. The coefficient of variation (CV) for analytical imprecision for serum cortisol was 5.5% within and 10.9% between assay. For urinary free cortisol excretion, the within-assay CV was 7.9% and the between-assay CV was 12.1%. Urinary creatinine was measured using an autoanalyzer (Cobas-bio; Roche Products Ltd, Welwyn Garden City; Herts, UK). The intra-assay and interassay CVs were 1.92% and 4.9%, respectively.

Data Analysis
The study was powered at 80% with a sample size of 14 in order to detect a 20% difference in the overnight urinary cortisol/creatinine ratio. All data were transformed logarithmically before analysis in order to normalize their distribution. Data were analyzed using appropriate software (Statgraphics; STSC Software Group; Rockville, MD). Comparisons were made by a multifactorial analysis of variance using subject, treatment, and period as factors. This was followed by Bonferroni multiple-range testing with confidence intervals (CIs) set at 95% in order to obviate multiple pairwise comparisons. Hence, all comparisons are reported as being significant (p < 0.05, 2-tailed) or not significant. 95% CIs for differences between treatments were also calculated.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Significant (p < 0.05) suppression of overnight or early morning corrected urinary cortisol/creatinine ratio and serum cortisol occurred with each treatment containing FP, compared to placebo treatment (Fig 1 ). Furthermore, significant (p < 0.05) additional suppression occurred when comparing FP by pMDI alone to FP by pMDI with spacer (Table 1 ). This amounted to a twofold difference for effect on 8:00 AM serum cortisol and overnight urinary cortisol/creatinine ratio.



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  		Figure 1. Values are shown for effects of treatment with placebo, FP by pMDI alone (2 mg ex-valve, 1.76 mg ex-actuator), or FP by pMDI with Volumatic 750-mL spacer on parameters of adrenal suppression. Geometric means and 95% CIs for within treatment effects are shown. For each parameter, there were significant differences between placebo vs FP by pMDI alone vs FP by pMDI with spacer.

 

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  		Table 1. Geometric Fold Differences Between Treatments*

 
Geometric means for within-treatment effects (95% CI) were as follows: (1) overnight urinary cortisol/creatinine ratio (nmol/mmol) for placebo treatment, 7.81 (5.22–11.67); FP by pMDI, 2.15 (1.44–3.21); FP by pMDI with spacer, 1.11 (0.74–1.65); (2) early morning urinary cortisol/creatinine ratio (nmol/mmol) for placebo treatment, 20.15 (10.07–40.30); FP by pMDI, 3.44 (1.72–6.89); and FP by pMDI with spacer, 1.28 (0.64–2.55); and (3) 8:00 AM serum cortisol (nmol/l) for placebo treatment, 427.9 (290.2–631.0); FP by pMDI, 155.5 (105.5–229.3); and FP by pMDI with spacer 78.5 (53.3–115.8).

Individual data for uncorrected overnight urinary free cortisol are shown in Figure 2 to illustrate dispersion and outliers. There were no subjects in the placebo group who suppressed their urinary cortisol to < 10 nmol/10 h, compared to 6 of 14 subjects (43%) in the FP by pMDI alone group, and 12 of 14 patients (86%) in the FP by pMDI with spacer group.



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  		Figure 2. Individual values for uncorrected overnight urinary cortisol for each treatment. The addition of a spacer increased the number of values < 10 nmol/10 h (indicated by the dotted line) to 12 of 14 subjects (86%), compared to 6 of 14 subjects (43%) in the FP by pMDI alone group.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study confirms the hypothesis that the addition of a large volume spacer to a FP pMDI leads to significantly greater adrenal suppression, a sensitive marker of systemic bioactivity. For effects on 8:00 AM serum cortisol and overnight urinary cortisol, there was a twofold increase in mean suppression when using the spacer. This was mirrored by twice as many subjects in the spacer group suppressing their uncorrected urinary cortisol to < 10 nmol/10 h: 86% compared to 43%. As there is almost complete (99%) hepatic first-pass metabolism for swallowed FP,14 15 it can be deduced that the spacer produces a twofold increase in respirable dose delivery and subsequent lung bioavailability.

The degree of adrenal suppression will be determined by circulating levels of exogenous corticosteroid (FP) in terms of effects on hypothalamic and pituitary glucocorticoid receptors, ie, the long and short negative feedback loops, respectively. This, in turn, results in reduced secretion of corticotropin-releasing hormone, corticotropin, and cortisol. Hence, measuring adrenal suppression is a good surrogate for evaluating the absorption of FP from the lung, and it is recognized as a reliable way of assessing systemic bioactivity of an inhaled corticosteroid.16 An overnight or early-morning waking collection of urinary free cortisol is simple for the patient to collect, and it is as sensitive as a 24-h collection, particularly when corrected for creatinine excretion, as in this study.17 18 Although measurement of a spot 8:00 AM serum cortisol level is considered to be a less sensitive marker than urinary cortisol in assessing basal adrenal function, we still observed suppression to a comparable degree as with overnight urinary cortisol. The washout period of 5 days (120 h) was chosen to exceed five elimination half-lives for FP (70 h). It has been shown that a washout period of 3 days is sufficient to allow recovery of adrenal suppression after repeated steady-state dosing with FP.19

In vitro and in vivo studies have shown spacer devices to increase the respirable dose delivered to the lung. In vitro impactor data with budesonide pMDI using an anatomical throat model has shown the 750 mL Nebuhaler (Astra Pharmaceuticals; Herts, UK) plastic spacer to produce a twofold increase in the respirable fraction (as percent of nominal dose ex-valve) from 20 to 40%.4

In vivo experience with radiolabeled teflon-coated particles has shown that addition of a Nebuhaler increased the lung dose from 9 to 21%.3 This fits with pharmacokinetic data using charcoal block in healthy subjects, where pulmonary bioavailability of budesonide was almost doubled, from 33% with a Nebuhaler compared to 18% with pMDI alone.20 In vivo pharmacokinetic data have shown that the respirable dose of a hydrofluoroalkane formulation of salbutamol pMDI increased by 50% when adding in a Volumatic spacing device.21 Further in vivo evidence in asthmatic patients was obtained in a study in which the patients received budesonide in either low (400 µg/d) or high (1600 µg/d) dosages, each for 2 weeks via pMDI alone, via pMDI with tube spacer, and via pMDI with Nebuhaler.5 By calculating the relative potency ratios, Toogood et al5 concluded that the addition of a large volume spacer was associated with an approximate twofold improvement in antiasthmatic efficacy, while accompanied by a similar twofold increase in systemic suppression of early morning serum cortisol and blood eosinophils. No comparable in vivo data are available for FP given via a large volume spacer compared to pMDI alone, although in vitro impactor studies have shown FP by pMDI to deliver approximately 35% as fine particle fraction of the nominal dose.22

Several studies in healthy and asthmatic subjects have demonstrated dose-related adrenal suppression with single and chronic dosing with FP by pMDI alone.23 24 25 26 27 However, surprisingly little is known about the effects of spacer use on systemic bioactivity when compared to pMDI use alone. Abstracted data in healthy volunteers evaluated the effect on early morning (9:00 AM) serum cortisol of two doses of FP (2 mg and 4 mg) via a Volumatic spacer, with suppression of 72% and 86%, respectively, although no comparison to pMDI alone was made.28

More data are available regarding the effect of spacer use on systemic bioactivity in subjects receiving beclomethasone dipropionate. Spacer use seems to reduce adrenal suppression, presumably by reducing oral bioavailability, secondary to the lower degree of hepatic first-pass metabolism with beclomethasone.7 9 10 11 Studies with budesonide with a Nebuhaler have revealed more conflicting results,8 9 although one would expect a spacer to increase its systemic bioavailability due to its higher hepatic first-pass metabolism (90%),29 as compared to 60 to 70% with beclomethasone.13

We recognize the limitations of our study. We used the highest recommended daily dose of FP (1.76 mg), although we did not intend to evaluate the clinical relevance of the degree of adrenal suppression. In addition, our study was not designed to examine the clinical relevance of large volume spacer use in patients with asthma, which would require larger subject numbers, evaluation of efficacy, as well as dynamic testing of adrenal reserve using cosyntropin or corticotropin-releasing factor. Furthermore, our subjects had normal lung function, and it is possible that lung deposition of inhaled corticosteroid may be altered in patients with asthma. Pharmacokinetic data exist for nebulized salbutamol, suggesting that baseline airway caliber can significantly reduce the lung dose of salbutamol in patients with severe asthma, amounting to a 45% fall in lung dose in relation to a 41% reduction in predicted normal FEV1.30 Thus, patients with more severe asthma may in effect be protected from systemic adverse effects, and they have a more favorable therapeutic ratio. It is therefore not possible to draw any conclusions regarding the absolute degree of adrenal suppression by studying healthy volunteers. Nevertheless, we believe our data in healthy subjects to be valid, as altered airway caliber would not influence the relative ratio in systemic bioactivity when comparing pMDI alone to pMDI with spacer. Finally, given the long half-life of FP (approximately 14 h), which is > 12-h dosing interval, drug accumulation will occur at steady state.15 23 Hence, the results of a single-dose study are likely to be an underestimate of the degree of suppression at steady state.31

In conclusion, although the use of a spacer, by increasing pulmonary deposition, may lead to greater clinical efficacy, the trade-off may be increased systemic adverse effects, as shown by Toogood et al5 with beclomethasone. The use of a spacer may augment or attenuate this adverse effect, and this study has demonstrated the former with FP, due to its negligible oral bioavailability. However, spacer use does confer other benefits, such as reduced oral candidiasis and ease of use when compared to a pMDI alone; for an individual patient, the balance between these risks and benefits must always be considered.


   Acknowledgements
 
The authors wish to thank Mrs. L McFarlane for performing the biochemical assays.


   Footnotes
 
Abbreviations: CI = confidence interval; CV = coefficient of variation; FP = fluticasone propionate; pMDI = pressurized metered-dose inhaler

This study was funded by a University of Dundee research grant and received no funding from the pharmaceutical industry.

Received for publication February 26, 1999. Accepted for publication May 14, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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