Elsevier

The Lancet

Volume 356, Issue 9229, 12 August 2000, Pages 556-561
The Lancet

Early Report
Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study

https://doi.org/10.1016/S0140-6736(00)02581-2Get rights and content

Summary

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 μg intravenous dose or 1000 μg 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% Cl 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.

Introduction

Since their introduction almost 30 years ago, inhaled corticosteroids have played a central part in the treatment of asthma. These drugs have almost entirely replaced maintenance oral corticosteroids, which had major adverse effects. Inhaled corticosteroids, because of topical application, have a substantially better therapeutic index than oral steroids.1, 2 Further improvements have been seen because of reduced oral bioavailability for newer inhaled coricosteroids. About 20% of the total inhaled dose from most metered-dose inhalers is deposited in the lungs and 80% stays in the oropharynx and is swallowed.3 Molecules with a high hepatic first-pass metabolism and low oral bioavailability, such as fluticasone propionate, therefore, have lower systemic exposure than other inhaled corticosteroids.4, 5, 6 For fluticasone propionate, any systemic activity results from absorption of the drug deposited in the lungs and its oral bioavailability is negligible.

Fluticasone propionate has a high therapeutic index and efficacy.7, 8 The drug has been used successfully for several years for all severities of asthma and has proved to be well tolerated. No clinically important systemic effects are reported for the normal therapeutic dose range.7, 8, 9, 10 By contrast, pharmacokinetic studies have suggested hypothalamic-pituitary-adrenal suppression with higher doses. However, those studies involved normal volunteers5, 11, 12, 13, 14, 15 or patients who had mild asthma and were receiving inappropriately high doses, well in excess of those needed to control their disease.16, 17, 18 In patients with moderate or severe asthma requiring higher doses of inhaled corticosteroids, factors such as airflow obstruction and ventilation-perfusion mismatch could alter drug deposition in the lung and change systemic absorption.

To clarify the safety of higher doses of fluticasone propionate in asthma, we studied the pharmacokinetics and pharmacodynamics of the drug in patients with moderately severe asthma compared with normal controls in a randomised double-blind, double-dummy, crossover design (figure 1).

Section snippets

Study population

We recruited individuals from outpatient clinics at the North West Lung Centre, who had physician-diagnosed asthma, gave written informed consent, and were aged between 20 years and 65 years. The inclusion criteria included forced expiratory volume in 1 s (FEV1) lower than 75% at screening, previous bronchodilator use, and a stable condition on high-dose inhaled corticosteroids (beclomethasone dipropionate [BDP] 2000 μg/day or budesonide 1600 μg/day). For each patient, we selected healthy

Results

Of 18 patients with asthma and 16 healthy volunteers screened, 11 and 13, respectively, entered the study (figure 1). One patient with asthma did not fulfil the lung-function entry criteria on the first sampling day and did not continue. One control attended the sampling day for inhaled fluticasone propionate, but refused to attend for the intravenous study day. One control had an extravasation at the intravenous site and the data were omitted from analysis. Ten patients with asthma and 11

Discussion

The systemic availability of inhaled fluticasone propionate was more than halved in asthma patients compared with healthy controls. As a consequence, less hypothalamic-pituitary-adrenal suppression was seen after high doses at steady-state.

Investigations into the potential systemic effects of inhaled corticosteroids have concentrated on four main areas: hypothalamic-pituitary-adrenal-axis function, bone density, growth in children, and cataracts. Several confounding factors make a precise

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