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

Chest. 1999 Oct;116(4):935-40. doi: 10.1378/chest.116.4.935.


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 microg ex-valve, 220 microg ex-actuator); (2) eight puffs of FP by pMDI, 250 microg, 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Androstadienes / administration & dosage*
  • Androstadienes / adverse effects
  • Androstadienes / pharmacokinetics
  • Anti-Asthmatic Agents / administration & dosage*
  • Anti-Asthmatic Agents / adverse effects
  • Anti-Asthmatic Agents / pharmacokinetics
  • Asthma / blood
  • Asthma / drug therapy*
  • Biological Availability
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Equipment Design
  • Fluticasone
  • Humans
  • Hydrocortisone / blood
  • Nebulizers and Vaporizers


  • Androstadienes
  • Anti-Asthmatic Agents
  • Fluticasone
  • Hydrocortisone