BACKGROUND:Fluticasone furoate (drug code GW685698) is an enhanced-affinity glucocorticoid that has been developed for the treatment of allergic rhinitis. OBJECTIVES: The objectives of this study were to estimate the absolute bioavailability of fluticasone furoate nasal spray and to describe the intranasal (IN) and IV pharmacokinetics of fluticasone furoate in healthy subjects. METHODS: This was a single-center, randomized, open label, 2-period crossover study. Healthy male and female subjects were randomized to receive supra-therapeutic doses of fluticasone furoate 880 microg IN qSh for 10 doses in 1 treatment period, and a single IV dose of 250 pg fluticasone furoate given as an infusion over 20 minutes in the other treatment period. Each treatment period was separated by a 4- to 5-day washout period. Blood sampling was carried out over 8 hours following the final IN dose and 24 hours following the IV dose to determine plasma fluticasone furoate concentrations. Plasma samples were analyzed for fluticasone furoate using online solid-phase extraction with high-performance liquid chromatography with tandem mass-spectrometric detection. The lower limit of quantification was 10 pg/mL. The sample size was based primarily on logistical considerations. Sample-size sensitivity was assessed by estimating the 90% CI for the absolute bioavailability of IN fluticasone furoate, based on different estimated bioavailabilities and within-subject SDs. The following pharmacokinetic parameters were derived: IN administration: AUC from time 0 to the end of the dosing interval (AUC(0-tau)), AUC(0-t), C(max), and T(max); IV administration: AUC(0-infinity), AUC(0-t), t(1/2), C(max), T(max), total systemic clearance, and volume of distribution at steady state. RESULTS:A total of 16 subjects were included in the study. Their mean age was 27.8 years (range, 19-45 years), and their mean body weight was 72.84 kg (range, 55.3-97.2 kg). The geometric mean AUC(0-tau) for 880 microg IN was 74.9 pg x mL/h and geometric mean AUC(0-infinity) for 250 microg IV was 4259 pg x mL/h. The geometric mean of the absolute bioavailability of fluticasone furoate nasal spray in these healthy subjects was 0.50% (90% CI, 0.34%-0.74%). The administration of large doses by the IN route did not elicit clinical concern. Three (19%) of 16 subjects reported adverse events (AEs) during the IN administration period, with 2 subjects experiencing dizziness and 1, toothache. Five (31%) subjects reported AEs during the IV administration period, with 3 subjects experiencing infusion-site or IV catheter-related events; 1 subject, dizziness; and 1 subject, headache. CONCLUSIONS: The geometric mean of the absolute bioavailability of fluticasone furoate 880 microg IN qSh for 10 doses in these healthy subjects was low--0.50%.
RCT Entities:
BACKGROUND:Fluticasone furoate (drug code GW685698) is an enhanced-affinity glucocorticoid that has been developed for the treatment of allergic rhinitis. OBJECTIVES: The objectives of this study were to estimate the absolute bioavailability of fluticasone furoate nasal spray and to describe the intranasal (IN) and IV pharmacokinetics of fluticasone furoate in healthy subjects. METHODS: This was a single-center, randomized, open label, 2-period crossover study. Healthy male and female subjects were randomized to receive supra-therapeutic doses of fluticasone furoate 880 microg IN qSh for 10 doses in 1 treatment period, and a single IV dose of 250 pg fluticasone furoate given as an infusion over 20 minutes in the other treatment period. Each treatment period was separated by a 4- to 5-day washout period. Blood sampling was carried out over 8 hours following the final IN dose and 24 hours following the IV dose to determine plasma fluticasone furoate concentrations. Plasma samples were analyzed for fluticasone furoate using online solid-phase extraction with high-performance liquid chromatography with tandem mass-spectrometric detection. The lower limit of quantification was 10 pg/mL. The sample size was based primarily on logistical considerations. Sample-size sensitivity was assessed by estimating the 90% CI for the absolute bioavailability of IN fluticasone furoate, based on different estimated bioavailabilities and within-subject SDs. The following pharmacokinetic parameters were derived: IN administration: AUC from time 0 to the end of the dosing interval (AUC(0-tau)), AUC(0-t), C(max), and T(max); IV administration: AUC(0-infinity), AUC(0-t), t(1/2), C(max), T(max), total systemic clearance, and volume of distribution at steady state. RESULTS: A total of 16 subjects were included in the study. Their mean age was 27.8 years (range, 19-45 years), and their mean body weight was 72.84 kg (range, 55.3-97.2 kg). The geometric mean AUC(0-tau) for 880 microg IN was 74.9 pg x mL/h and geometric mean AUC(0-infinity) for 250 microg IV was 4259 pg x mL/h. The geometric mean of the absolute bioavailability of fluticasone furoate nasal spray in these healthy subjects was 0.50% (90% CI, 0.34%-0.74%). The administration of large doses by the IN route did not elicit clinical concern. Three (19%) of 16 subjects reported adverse events (AEs) during the IN administration period, with 2 subjects experiencing dizziness and 1, toothache. Five (31%) subjects reported AEs during the IV administration period, with 3 subjects experiencing infusion-site or IV catheter-related events; 1 subject, dizziness; and 1 subject, headache. CONCLUSIONS: The geometric mean of the absolute bioavailability of fluticasone furoate 880 microg IN qSh for 10 doses in these healthy subjects was low--0.50%.