Single-dose and steady-state pharmacokinetic and pharmacodynamic evaluation of therapeutically clinically equivalent doses of inhaled fluticasone propionate and budesonide, given as Diskus((R)) or Turbohaler((R)) dry-powder inhalers to healthy subjects

Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosin g in the same subjects are scarce. The objective of this study was to compa re the PK/PD properties of clinically equivalent, single, and multiple dose s of dry-powder formulations of inhaled fluticasone propionate (FP, 200 and 500 mug via Diskus (R)) and budesonide (BUD, 400 and 1000 mug via Turbohal er (R)). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a si ngle dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was moni tored as the pharmacodynamic surrogate marker. Peak serum concentrations fo llowing., single and multiple dosing were observed 10 to 30 minutes after i nhalation for BUD and 30 to 90 minutes after inhalation of FP with no influ ence of dose or dosing regimen. After a single dose of 1000 mug BUD and 500 mug FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively . Using previously reported intravenous data, the mean absorption times (MA T) were calculated to be around 2 hours and 7 hours for BUD and FP respecti vely. On average, the area under the curve (AUC) at steady state (day 5) wa s up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas AUC estimates were 50% to 80% higher for FP at steady state, indicating accumulation. However, the steady-state C-ma x values were seven to eight times and A UC values three to four times high er for BUD than for FP Comparison of active treatment data with placebo sho wed that CCS after a single dose was not pronounced for any of the doses/dr ugs studied. On day 5, both doses of BUD caused statistically significant s uppression (CCS of 19% for the 400 mug dose and 36% for the 1000 mug dose). For FP, only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 mug dose and 27% for the 500 mug dose). C ompared to BUD, FP has slower pulmonary absorption and slower elimination k inetics. However, following inhalation of therapeutically equipotent, multi ple twice-daily doses in healthy subjects, the systemic effects of FP deliv ered ilia Diskus (R) on AUC(24) serum cortisol were relatively low and simi lar to those of BUD delivered via Turbohaler (R). (C) 2001 the American Col lege of Clinical Pharmacology.