Comparison of pharmacokinetics and systemic effects of inhaled fluticasonepropionate in patients with asthma and healthy volunteers: a randomised crossover study

Background Inhaled corticosteroids are currently the cornerstone of asthma treatment. Some studies of high-dose fluticasone propionate in patients wit h no or mild asthma have, however, suggested substantial systemic absorptio n. We investigated the pharmacokinetics of fluticasone propionate in patien ts with asthma receiving appropriate doses for severity. Methods We did a double-blind, randomised, crossover study in 11 patients w ith asthma and 13 matched healthy controls (age 20-65 years; asthma patient s forced expiratory volume in 1 s <75% and stable on high-dose inhaled cort icosteroids), Patients received one 1000 mu g intravenous dose or 1000 mu g daily for 7 days inhaled (via spacer device) fluticasone propionate, In th e 12 h after dosing, we monitored plasma fluticasone propionate and cortiso l concentrations by mass spectrometry and competitive immunoassay with use of direct chemiluminescence. Analysis was by intention to treat. Findings After inhalation, geometric mean values were significantly lower i n the asthma group than in controls for fluticasone propionate plasma area under curve (1082 [95% CI 850-1451] vs 2815 pg mL(-1) h(-1) [2262-3949], -6 2% difference [45-72]; p<0.001), maximum concentrations (117 [91-159] vs 38 3 pg/mL [302-546], -68% [-50 to -81]; p<0.001), and systemic bioavailabilit y (10.1 [7.9-14.0] vs 21.4% [15.4-32 2], -54% [-27 to -70]; p=0.001). Intra venous-dose clearance, volume of distribution at steady state, plasma half- life, and mean residence time, were similar in the two groups. Less suppres sion of plasma cortisol concentrations was seen in the asthma group than in controls 4-12 h after inhaled fluticasone propionate. Interpretation Systemic availability of fluticasone propionate is substanti ally less in patients with moderate to severe asthma than in healthy contro ls. Inhaled corticosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for disease severi ty, and not in normal volunteers.