Evaluation of the effect of a large volume spacer on the systemic bioactivity of fluticasone propionate metered-dose inhaler

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 par in a randomized sequence: (1) eight-puffs of FP by pMDI, 1.76 mg (250 mu g ex-valve, 220 mu g ex-actuator); (2) eight puffs of FP by pPMDI, 250 mu g, 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 1 1 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.