L Lu un ng g d de ep po os si it ti io on n o of f b bu ud de es so on ni id de e f fr ro om m T Tu ur rb bu uh ha al le er r¤ ¤ i is s t tw wi ic ce e t th ha atABSTRACT: The pulmonary and systemic availability of budesonide after inhalation from a dry powder inhaler, Turbuhaler®, and from a pressurized metered-dose inhaler (P-MDI) were compared in healthy volunteers. Two different methods were used to assess pulmonary availability: 1) calculated from the systemic availability corrected for an oral availability of 13% (n=24); and 2) after blocking of gastrointestinal absorption by administration of a charcoal suspension (n=13). An intravenous infusion of budesonide was used as a reference.The systemic availability of budesonide, calculated as a geometric mean and expressed as percentage of the metered dose, was 38% for Turbuhaler® and 26% for P-MDI. The pulmonary availability, calculated using the first method, was 32% and 15% for Turbuhaler® and P-MDI, respectively; and, using the second method, 32% and 18%, respectively.The results of the present study indicate that administration of budesonide via Turbuhaler® gives rise to a lung deposition which is approximately twice that of a P-MDI, with less variability, but that systemic availability is only increased by approximately 50%. Thus, the present data suggest that by administrating budesonide via Turbuhaler®, instead of a P-MDI, the same degree of asthma control can be achieved with a lower dose, which, in turn, reduces the risk of undesired systemic effects.

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.

Aims The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation. Methods Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 mg ) of FP via DiskhalerA and repeated inhalations (1000 mg twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 mg FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values. Results The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6-18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20-65]% and 95 [93-97]% for the single and repeated doses, respectively. Conclusions To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.

Inhalation is a mainstay for treatment of asthma, and lung deposition can be seen as a surrogate marker for the ensuing clinical effects. Not only absolute lung deposition, but also its variability is of interest, as it indicates the range of expected lung deposition in an individual patient when prescribing the drug and the expected day-to-day variability when using it. A literature survey found 71 studies with relevant information on lung deposition and its variability. Further characteristics of the studies, such as if the subjects were healthy or asthmatics, adults or children, and what device that was used, were noted. In all, 187 data points were included. Variability in lung deposition was depicted as a function of mean lung deposition; for the entire data set and for subsets thereof. Independent of device type or subject category high lung deposition was associated with low relative variability and vice versa. Using a published throat deposition model, the observed correlation of lung deposition variability to mean lung deposition could be explained as being determined largely by the extent of and variability in throat deposition. We hypothesize that throat deposition is the major determinant for lung deposition of an inhaled aerosol, and its absolute variability will largely be determined by the absolute variability in throat deposition. The relative variability in lung deposition will therefore tend to be high for low lung deposition and low for high lung deposition. Consequently, low relative variability in lung deposition can only be attained if high lung deposition is achieved.