Early ReportComparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study
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
References (30)
Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in relation to efficacy and safety
Respir Med
(1997)The human pharmacology of fluticasone propionate
Respir Med
(1990)- et al.
A randomised, double‐blind dose reduction study to compare the minimal effective dose of budesonide Turbohaler and fluticasone propionate Diskhaler
J Allergy Clin Immunol
(1997) - et al.
Determination of the glucocorticoid flutiasone propionate in plasma by automated solid‐phase extraction and liquid chromatography‐tandem mass spectrometry
J Chromatogr B Biomed Sci Appl
(1998) Corticosteroid treatment of asthma: now at the crossroads
Respir Med
(1999)- et al.
Efficacy and safety of inhaled corticosteroids in asthma
Am Rev Respir Dis
(1993) Pharmacokinetics of inhaled drugs
Clin Pharmacol
(1996)Methodological studies on lung depostion: evaluation of inhaler devices and absorption mechanisms
- et al.
Oral bioavailability of fluticasone propionate in healthy subjects
Br J Clin Pharmacol
(1996) - et al.
Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year
Thorax
(1993)
High dose fluticasone propionate, 1 mg daily versus fluticasone propionate, 2 mg daily, or budesonide, 1·6 mg daily, in patients with chronic severe asthma
Eur Respir J
Adrenal function and high dose inhaled corticosteroids for asthma
Arch Dis Child
An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers
Eur J Clin Pharmacol
An assessment of the systemic activity of single doses of inhaled fluticasone propionate in healthy volunteers
Br J Clin Pharmacol
A dose‐response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbohaler
Eur J Clin Pharmacol
Cited by (204)
An effective PBPK model predicting dissolved drug transfer from a representative nasal cavity to the blood stream
2022, Journal of Aerosol ScienceCitation Excerpt :However, the effects of different physiological aspects, drug formulations, and patient-related factors are still poorly understood. For example, changes in lung physiology and anatomy in healthy and diseased subjects affect the pharmacokinetic (PK) behaviour of some corticosteroids while that of others is unchanged (Brutsche et al., 2000; Singh et al., 2003). A large number of mass-transfer parameters are responsible for the rate of drug absorption, once the drug is deposited in the nasal cavity (Huang et al., 1985; Ohwaki et al., 1985; Su et al., 1985).
Serum Inhaled Corticosteroid Detection for Monitoring Adherence in Severe Asthma
2021, Journal of Allergy and Clinical Immunology: In PracticeDrivers of absolute systemic bioavailability after oral pulmonary inhalation in humans
2021, European Journal of Pharmaceutics and BiopharmaceuticsPharmacokinetics and pharmacodynamics of inhaled corticosteroids for asthma treatment
2019, Pulmonary Pharmacology and TherapeuticsAdrenal suppression with inhaled corticosteroids: the seed and the soil
2018, The Lancet Respiratory Medicine