Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1          Pharmacodynamic properties
Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use . Corticosteroids

ATC Code: R01AD08

Fluticasone propionate has been shown to reduce inflammatory mediators in both the early and late phase reactions of allergic rhinitis.
Once daily dosing with 200µg fluticasone propionate is sufficient to help relieve symptoms (particularly nasal congestion) for up to 24 hours.

Fluticasone propionate is a glucocorticosteroid which has potent anti- inflammatory activity by acting via the glucocorticoid receptor. However, when used at up to four times the recommended daily dose on the nasal mucosa, has no detectable systemic activity and causes little or no hypothalamic-pituitary-adrenal axis suppression following intranasal administration.

Following intranasal dosing of fluticasone propionate, (200mcg/day) no significant change in 24h serum cortisol AUC was found compared to placebo (ratio1.01, 90%CI 0.9-1.14).

In a 1-year randomised, double-blind, placebo-controlled, parallel group growth study in pre-pubescent children aged 3 to 9 years (56 patients receiving intranasal fluticasone propionate and 52 receiving placebo,) no statistically significant difference in growth velocity was observed in patients receiving intranasal fluticasone propionate (200 micrograms per day nasal spray) compared to placebo.
The estimated growth velocity over one year of treatment was 6.20 cm/year 
(SE=0.23) in the placebo group and 5.99 cm/year (SE=0.23) in the fluticasone propionate group; the mean difference between treatments in growth velocity after one year was 0.20 cm/year (SE=0.28, 95% CI= -0.35, 0.76). No evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, respectively.

Pharmacokinetic Properties

5.2          Pharmacokinetic properties
Absorption: Following intranasal dosing of fluticasone propionate, (200 mcg/day) steady-state maximum plasma concentrations were not quantifiable in most subjects (<0.01ng/mL). The highest Cmax observed was 0.017ng/mL.
Direct absorption in the nose is negligible due to the low aqueous solubility with the majority of the dose being eventually swallowed. When administered orally the systemic exposure is <1% due to poor absorption and pre-systemic metabolism. The total systemic absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible.
Distribution: Fluticasone propionate has a large volume of distribution at steady-state (approximately 318L). Plasma protein binding is moderately high (91%).
Metabolism: Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Care should be taken when co-administering potent CYP3A4 inhibitors such as ketoconazole and ritonavir as there is potential for increased systemic exposure to fluticasone propionate.
Elimination: The elimination rate of intravenous administered fluticasone propionate is linear over the 250-1000 mcg dose range and are characterized by a high plasma clearance (CL=1.1L/min). Peak plasma concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations were associated with the 7.8h terminal half-life. The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.