Chemical formula: C₂₂H₂₇F₃O₄S Molecular mass: 444.51 g/mol
Fluticasone propionate as a glucocorticoid has anti-inflammatory and vasoconstrictive features.
Applied topically on the skin it suppresses inflammatory reactions and symptoms although without curing the underlying disorder. Systemic absorption through the subcutaneous tissues is low.
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in a reduction of both symptoms and exacerbations of asthma, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically.
Fluticasone furoate undergoes incomplete absorption and extensive first-pass metabolism 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 (<10 pg/ml). The absolute bioavailability for intranasal fluticasone furoate is 0.50%, such that less than 1 microgram of fluticasone furoate would be systemically available after administration of 110 micrograms.
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.
Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 l/h) from systemic circulation principally by hepatic metabolism to an inactive 17β-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 17β-carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.
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.
In the majority of patients fluticasone furoate is not quantifiable (<10 pg/ml) following intranasal dosing of 110 micrograms once daily. Quantifiable levels were observed in 15.1% of paediatric patients following intranasal dosing of 110 micrograms once daily and only 6.8 % of paediatric patients following 55 micrograms once daily. There was no evidence for higher quantifiable levels of fluticasone furoate in younger children (less than 6 years of age). Median fluticasone furoate concentrations in those subjects with quantifiable levels at 55 micrograms were 18.4 pg/ml and 18.9 pg/ml for 2-5 yrs and 6-11 yrs, respectively.
At 110 micrograms, median concentrations in those subjects with quantifiable levels were 14.3 pg/ml and 14.4 pg/ml for 2-5 yrs and 6-11 yrs, respectively. The values are similar to those seen in adults (12+) where median concentrations in those subjects with quantifiable levels were 15.4 pg/ml and 21.8 pg/ml at 55 micrograms and 110 micrograms, respectively.
Only a small number of elderly patients (≥65 years, n=23/872; 2.6%) provided pharmacokinetic data. There was no evidence for a higher incidence of patients with quantifiable fluticasone furoate concentrations in the elderly, when compared with the younger patients.
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.
There are no data with intranasal fluticasone furoate in patients 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 Cmax (42%) and AUC(0-∞) (172 ) and a modest (on average 23) decrease in cortisol levels in patients 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 of 110 micrograms of intranasal fluticasone furoate in this patient population would not be expected to result in suppression of cortisol.
Pharmacokinetic data for the rat and the dog indicate rapid elimination and extensive metabolic clearance. Bioavailability is very low after topical or oral administration, due to limited absorption through the skin or from the gastrointestinal tract, and because of extensive first-pass metabolism. Distribution studies have shown that only minute traces of orally administered compound reach the systemic circulation, and that any systemically available radiolabel is rapidly eliminated in the bile and excreted in the faeces.
Fluticasone propionate does not persist in any tissue, and does not bind to melanin. The major route of metabolism is hydrolysis of the S-fluoromethyl carbothioate group, to yield a carboxylic acid (GR36264), which has very weak glucocorticoid or anti-inflammatory activity. In all test animal species, the route of excretion of radioactivity is independent of the route of administration of radiolabelled fluticasone propionate.
Excretion is predominantly faecal and is essentially complete within 48 hours. In man, too, metabolic clearance is extensive, and elimination is consequently rapid.
Thus, drug entering the system circulation via the skin will be rapidly inactivated. Oral bioavailability approaches zero, due to poor absorption and extensive first-pass metabolism. Therefore, systemic exposure to any ingestion of the topical formulation will be low.
In healthy subjects the mean systemic bioavailability of flixotide is 28.6%. In patients with asthma (FEV1 <75% predicted) the mean systemic absolute bioavailability was reduced by 62%. Systemic absorption occurs mainly through the lungs and has been shown to be linearly related to dose over the dose range 500 to 2000 micrograms. Absorption is initially rapid then prolonged and the remainder of the dose may be swallowed.
Absolute oral bioavailability is negligible (<1%) due to a combination of incomplete absorption from the GI tract and extensive first-pass metabolism.
87-100% of an oral dose is excreted in the faeces, up to 75% as parent compound. There is also a non-active major metabolite.
After an intravenous dose, fluticasone propionate is extensively distributed in the body. The very high clearance rate indicates extensive hepatic clearance.
Findings in general toxicology studies were similar to those observed with other glucocorticoids and are associated with exaggerated pharmacological activity. These findings are not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure. No genotoxic effects of fluticasone furoate have been observed in conventional genotoxicity tests. Further, there were no treatment-related increases in the incidence of tumours in two year inhalation studies in rats and mice.
Toxicology has shown only those class effects typical of potent corticosteroids, and these only at doses greatly in excess of that proposed for therapeutic use. No novel effects were identified in repeat dose toxicity tests, reproductive studies or teratology studies. Fluticasone propionate is devoid of mutagenic activity in vitro and in vivo and showed no tumorigenic potential in rodents. It is both non-irritant and non-sensitising in animal models.
Subcutaneous embryofetal development studies in mouse and rat at 45 and 100 mcg/kg, respectively (approximately equivalent to 4 and 6 times the maximum recommended daily inhaled dose of 500 mcg twice daily in adults based on mouse and rat plasma levels of 486 and 710 pg/mL, respectively) resulted in fetal developmental toxicity characteristic of a potent corticosteroid, including cleft palate and embryonic fetal growth retardation, at doses that caused maternal toxicity. The no effect level for these finding in rat were associated with systemic exposures approximately 3 times the highest clinical exposure based on rat plasma level of 310 pg/mL. In the rabbit, fetal weight reduction and cleft palate occurred at a maternally toxic subcutaneous dose of 4 mcg/kg (less than 1.4 times the maximum recommended inhaled dose of 500 mcg twice daily based on rabbit plasma level of 149 pg/mL). However, fluticasone propionate administered via inhalation to rats did not induce teratogenicity at maternal toxic doses associated with exposures 13 times the human exposure achieved with the maximum recommended daily inhaled dose based on rat plasma level of 1430 pg/mL.
The non-CFC propellant, HFA 134a, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.
The use of HFA 134a as a propellant has not altered the toxicity profile of fluticasone propionate compared to that using the conventional CFC propellant.
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