Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate 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 with no or mild asthma have, however, suggested substantial systemic absorption. We investigated the pharmacokinetics of fluticasone propionate in patients with asthma receiving appropriate doses for severity. METHODS: We did a double-blind, randomised, crossover study in 11 patients with asthma and 13 matched healthy controls (age 20-65 years; asthma patients forced expiratory volume in 1 s <75% and stable on high-dose inhaled corticosteroids). Patients received one 1000 microg intravenous dose or 1000 microg daily for 7 days inhaled (via spacer device) fluticasone propionate. In the 12 h after dosing, we monitored plasma fluticasone propionate and cortisol 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 in 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], -62% difference [45-72]; p<0.001), maximum concentrations (117 [91-159] vs 383 pg/mL [302-546], -68% [-50 to -81]; p<0.001), and systemic bioavailability (10.1 [7.9-14.0] vs 21.4% [15.4-32.2], -54% [-27 to -70]; p=0.001). Intravenous-dose clearance, volume of distribution at steady state, plasma half-life, and mean residence time, were similar in the two groups. Less suppression 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 substantially less in patients with moderate to severe asthma than in healthy controls. Inhaled corticosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for disease severity, and not in normal volunteers.

Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo.

It has been hypothesized that regular inhaled beta2-agonist therapy causes desensitization of beta2-receptors. The aim of this study was to define whether beta2-receptor desensitization occurs after treatment with the long-acting beta2-agonist salmeterol, assessed by measuring the bronchodilator response to cumulative repeated doses of inhaled salbutamol before and after treatment. Forty nine stable adult patients with asthma were randomized to receive either salmeterol 50 microg b.d. or placebo b.d. from an Accuhaler for 4 weeks after an initial 2 week run-in period without beta2-agonists. All patients were receiving inhaled corticosteroids. Bronchodilator responsiveness to cumulative repeated doses of inhaled salbutamol were measured before and 12 and 36 h after the last dose of study treatment. The primary efficacy endpoint was the peak forced expiratory volume in one second (FEV1) response before and after treatment. There were no significant differences between the two treatment groups in the absolute peak FEV1 or maximal peak expiratory flow (PEF) results 12 or 36 h after the last dose of study treatment. Significantly higher clinic lung function and diary card parameters were noted in the salmeterol group when compared to the placebo-treated patients, demonstrating the beneficial effects of regular salmeterol. Regular salmeterol usage did not lead to reduced efficacy of usual or higher than usual doses of salbutamol.