Chest
Volume 116, Issue 4, October 1999, Pages 935-940
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Clinical Investigations
ASTHMA
Evaluation of the Effect of a Large Volume Spacer on the Systemic Bioactivity of Fluticasone Propionate Metered-Dose Inhaler

https://doi.org/10.1378/chest.116.4.935Get rights and content

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 pmin a randomized sequence: (1) eight puffs of FP by pMDI, 1.76 mg (250μ g 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.

Section snippets

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

Results

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.

Geometric means for

Discussion

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

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      Citation Excerpt :

      The primary endpoint was overnight urinary cortisol creatinine ratio. A sample size of 16 completed patients per protocol was chosen to power the study at 80% to detect a 20% difference in overnight urinary cortisol creatinine ratio, using data from a previous study which detected a 50% difference between spacer and pMDI with a sample size of 14 completed patients [22]. Data sets were analyzed for patients who completed the crossover study per protocol.

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

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