Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Abstract

Aims To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids. Methods Twenty-one subjects (13 healthy and 8 mild asthmatic patients) received uticasone propionate via a chloro¯uorocarbon-propelled pressurized metered-dose inhaler (pMDI) (healthy subjects only) and Diskus 1 and budesonide via Turbuhaler 1 , 1000 mg twice daily for 7 days. Intravenous doses (200 mg) of both compounds were used as references. Plasma concentrations of¯uticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC-MS-MS). Plasma concentrations of cortisol were determined by LC-MS every second hour for 24 h at baseline, and following each treatment. Results The volume of distribution was found to be larger and the elimination half-life and mean absorption time longer for¯uticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was signi®cantly higher than that of uticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% con®dence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of¯uticasone via pMDI was signi®cantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2-fold [1.7, 2.9] higher than that of¯uticasone pMDI and 3.4-fold [2.8, 4.0] higher than that of uticasone Diskus. In addition, the lung deposition of¯uticasone via pMDI was 1.5-fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was signi®cantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for¯uticasone pMDI, which was signi®cantly lower (ratio 0.32 [0.24, 0.42]) than that for¯uticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ signi®cantly between treatments with¯uticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]). Conclusions Budesonide and¯uticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for uticasone. Despite a signi®cantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of¯uticasone via pMDI and similar to that of¯uticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of¯uticasone and budesonide.

Treatment of exercise-induced asthma with beclomethasone dipropionate in children with asthma

“…A new formulation of hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP; QVAR TM ; 3M Pharmaceuticals, St. Paul, MN, USA) produces an extra-fine aerosol spray that, compared with conventional inhalers, increases the amount of drug delivered to the lungs [13][14][15][16][17][18][19][20]. Since more drug per puff is delivered to the site of the disease, it seems reasonable to assume that even very low doses of HFA-BDP will provide a significant therapeutic response.…”

Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

“…High lipophilicity increases both the GC uptake and retention in airway tissue (i.e., decelerates removal of GCs from airway tissue), and thereby enhances and prolongs anti-inflammatory efficacy of inhaled GCs in the airways (Brattsand, 1997). On the other hand, high lipophilicity can be a disadvantage in the peripheral tissues leading to enhanced distribution and retention, prolonged terminal plasma halflife, and accumulation (Thorsson et al, 1997(Thorsson et al, , 2001Lipworth and Jackson, 2000). Furthermore, highly lipophilic inhaled GCs have a low water solubility which may increase the GC fraction that is cleared by mucocilliary escalator before it is dissolved in airway fluid and absorbed into airway tissue and becomes available for cytosolic GC receptor (Edsbäcker, 2002).…”

Which factors affect the choice of the inhaler in chronic obstructive respiratory diseases?

“…Findings with this methodology generally replicate those obtained with the Andersen impactor device. Regarding DPIs, Turbuhaler delivers approximately 25e35% of the labelled dose to the lung, whereas the Diskus delivers about half this amount [15]. The lung deposition from Turbuhaler is significantly greater than from a pMDI [16].…”

“…Diskus has coarse particles combined with a lactose carrier that has limited capacity for generating fine particles [17]. Lung deposition is more consistent with Turbuhaler than with Diskus (coefficient of variation 20% vs. 40%) [15,18]. Other inhalers, such as NEXThaler, have demonstrated good performance despite the degree of bronchococonstriction and underlying disease.…”