Ansonide Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Fluticasone furoate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action.
Pharmacokinetics: Absorption: Fluticasone furoate undergoes extensive first-pass metabolism and incomplete absorption in the liver and gut resulting in negligible systemic exposure. The intranasal dosing of 110 micrograms once daily does not typically result in measurable plasma concentrations (less than 10 picograms/mL). The absolute bioavailability for fluticasone furoate administered as 880 micrograms three times per day (2640 micrograms total daily dose) is 0.50%.
Distribution: The plasma protein binding of fluticasone furoate is greater than 99%. Fluticasone furoate is widely distributed with volume of distribution at steady-state of, on average, 608 L.
Metabolism: Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 L/h) from systemic circulation principally by hepatic metabolism to an inactive 17 beta-carboxylic metabolite (GW694301X) by the cytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17 beta-carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.
Elimination: Elimination was primarily via the faecal route following oral and intravenous administration, indicative of excretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively.
Special Patient Populations: Elderly: Only a small number of elderly subjects (n=23/872; 2.6%) provided pharmacokinetic data. There was no evidence for a higher incidence of subjects with quantifiable fluticasone furoate concentrations in the elderly when compared to the younger subjects.
Children: Fluticasone furoate is typically not quantifiable (less than 10 picograms/mL) following intranasal dosing of 110 micrograms once daily. Quantifiable levels were observed in less than 16% of paediatric patients following intranasal dosing of 110 micrograms once daily and only less than 7% of paediatric patients following 55 micrograms once daily. There was no evidence for a higher incidence of quantifiable levels of fluticasone furoate in younger children (less than 6 years of age).
Renal Impairment: Fluticasone furoate is not detectable in urine from healthy volunteers after intranasal dosing. Less than 1% of dose-related material is excreted in urine and therefore, renal impairment would not be expected to affect the pharmacokinetics of fluticasone furoate.
Hepatic Impairment: There are no data on intranasal fluticasone furoate in subjects with hepatic impairment. Data are available following inhaled administration of fluticasone furoate (as fluticasone furoate or fluticasone furoate/vilanterol) to subjects with hepatic impairment that are also applicable for intranasal dosing. A study of a single 400 microgram dose of orally inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh B) resulted in increased C_max (42%) and AUC_(0-∞) (l72%) compared to healthy subjects. Following repeat dosing of orally inhaled fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (on average two-fold as measured by AUC_(0-24)) in subjects with moderate or severe hepatic impairment (Child-Pugh B or C) compared with healthy subjects. The increase in fluticasone furoate systemic exposure in subjects with moderate hepatic impairment (fluticasone furoate/vilanterol 200/25 micrograms) was associated with an average 34% reduction in serum cortisol compared with healthy subjects. There was no effect on serum cortisol in subjects with severe hepatic impairment (fluticasone furoate/vilanterol 100/12.5 micrograms). Based on these findings, the average predicted exposure for 110 micrograms of intranasal fluticasone furoate in patient population would not be expected to result in suppression of cortisol.
Other pharmacokinetic: Fluticasone furoate is typically not quantifiable (less than 10 picograms/mL) following intranasal dosing of 110 micrograms once daily. Quantifiable levels were only observed in less than 31% of patients aged 12 years and above and in less than 16% of paediatric patients following intranasal dosing of 110 micrograms once daily. There was no evidence for gender, age (including paediatrics), or race to be related to those subjects with quantifiable levels when compared to those without.