Fluticasone Furoate Nitto Mechanism of Action

Pharmacology: Mechanism of Action: Fluticasone furoate is a synthetic corticosteroid which exerts suppressive effects on allergic rhinitis and eosinophilic infiltration and has anti-inflammatory effects by stimulating the glucocorticoid receptor.
Suppressive effect on allergic rhinitis: In rat models of allergic rhinitis, nasal symptoms (sneezing and nose scratching) were suppressed with intranasal administration of fluticasone furoate, and the potency was similar to that of fluticasone propionate. Moreover, the duration of the effect against nose scratching was similar to that of fluticasone propionate, and the duration of the effect against sneezing was longer than that of fluticasone propionate.
Suppressive effect on eosinophilic infiltration: In actively sensitized rats, antigen-induced eosinophilic infiltration of the trachea was suppressed with intratracheal administration of fluticasone furoate, and the potency was similar to that of fluticasone propionate.
Anti-inflammatory effect: In rat and mouse models of delayed hypersensitivity, antigen-induced auricular edema was suppressed with topical application of fluticasone furoate to the auricle, and the potency was similar to that of fluticasone propionate.
Pharmacokinetics: Blood Level: Healthy adults: Regarding blood levels of fluticasone furoate when administered intranasally at 110, 220, and 440 µg^Note) as a single dose and once daily (440 µg/day^Note)) repeatedly for 7 days, the levels were below the lower limit of quantification (10 pg/mL) with single doses up to 220 µg. At 440 µg, the levels were slightly above the lower limit of quantification in 1 of 8 subjects who had received a single dose and in 3 of 8 subjects who had received repeated doses. In subjects whose blood levels exceeding the lower limit of quantification, the maximum plasma concentration in the subject who had received a single dose and the 3 subjects who had received repeated doses was 10.7-14.6 pg/mL.
Pediatric patients with perennial allergic rhinitis: The blood levels at 0.5-2.0 h after the dose on the last day of 12-week intranasal administration of fluticasone furoate at 55 µg once daily were below the lower limit of quantification (10 pg/mL) in most of the subjects. In subjects whose blood levels exceeding the lower limit of quantification, the plasma concentrations of 2 subjects in the 2 to <6 years group were 10.9 and 13.1 pg/mL, and those of 3 subjects in the 6 to <15 years group were 14.9-23.7 pg/mL.
Comparative study of systemic exposure: Either Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray (56 Sprays) or Allermist 27.5 μg metered nasal spray 56 sprays (reference product) was administered at a dose of 2 sprays (110 µg as fluticasone furoate) into each nostril in 36 healthy adult males in a crossover study, and plasma fluticasone furoate concentrations were then measured. As a result, the mean and maximum values for the maximum plasma concentrations (C_max) of unchanged drug at all measurement time points in all the subjects were confirmed to be below the prescribed acceptable limit (25 pg/mL).
Distribution: The human plasma protein binding rate was ≥99% in vitro.
Metabolism: Fluticasone furoate was mainly metabolized by CYP3A4 in the liver, and 17β-carboxylate was the main circulating metabolite with oral administration in healthy adult volunteers (data obtained from non-Japanese participants). (See Interactions).
Excretion: The main route of excretion was via the feces, and urinary excretion rates with oral administration and intravenous administration were approximately 1% and 2%, respectively (data obtained from non-Japanese participants).
Patients with Specific Backgrounds: Patients with hepatic impairment: Intranasal administration of fluticasone furoate in patients with hepatic impairment has not been evaluated.
Increases in C_max and area under the concentration-time curve (AUC) have been reported in patients with moderate hepatic impairment who inhaled a single dose of fluticasone furoate at 400 µg^Note) (data obtained from non-Japanese participants).
Drug-Drug Interaction: CYP3A4 inhibitors: In subjects receiving repeated intranasal administration of fluticasone furoate at 110 µg/day for 7 days, coadministration with the potent CYP3A4 inhibitor ketoconazole (orally administered at 200 mg once daily, not marketed in Japan) resulted in more subjects (6 of 20 subjects) with quantifiable fluticasone furoate blood concentrations compared to placebo (1 of 20 subjects). Following 7-day coadministration, the ratio (90% confidence interval in parentheses) of the weighted average for 24-h serum cortisol levels in ketoconazole group compared to that in placebo group was 0.95 (0.86-1.04) (data obtained from non-Japanese participants). (See Precautions for Co-administration under Interactions.)
^Note):The approved dosage of Fluticasone Furoate Nitto Nasal Spray 27.5 mcg/spray is 2 sprays (27.5 µg×2) per dose into each nostril once daily (110 µg/day) for adults and 1 spray (27.5 µg×1) per dose into each nostril once daily (55 µg/day) for children.