Fluticasone propionate is a synthetic, trifluorinated glucocorticoid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results.
The precise mechanisms of glucocorticoid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Glucocorticoids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of glucocorticoids may contribute to their efficacy in asthma.
Though highly effective for the treatment of asthma, glucocorticoids do not affect asthma symptoms immediately. However, improvement following inhaled administration of fluticasone propionate can occur within 24 hours of beginning treatment, although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When glucocorticoids are discontinued, asthma stability may persist for several days or longer.
Pharmacokinetics: Absorption: The activity of FLOVENT Inhalation Aerosol is due to the parent drug, fluticasone propionate. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. The systemic bioavailability of fluticasone propionate inhalation aerosol in healthy volunteers averaged about 30% of the dose delivered from the actuator.
Peak plasma concentrations after an 880-mcg inhaled dose ranged from 0.1 to 1.0 ng/mL.
Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.
Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17(beta)-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had approximately 2,000 times less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.
Excretion: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.
Special Populations: Formal pharmacokinetic studies using fluticasone propionate were not carried out in any special populations. In a clinical study using fluticasone propionate inhalation powder, trough fluticasone propionate plasma concentrations were collected in 76 males and 74 females after inhaled administration of 100 and 500 mcg twice daily. Full pharmacokinetic profiles were obtained from 7 female patients and 13 male patients at these doses, and no overall differences in pharmacokinetic behavior were found.
Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax averaged 11.9 pg/mL [range, 10.8 to 14.1 pg/mL] and AUC(0-[tgr ]) averaged 8.43 pg·hr/mL [range, 4.2 to 18.8 pg·hr/mL]). Fluticasone propionate Cmax and AUC(0-[tgr ]) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg·hr/mL (range, 1,207.1 to 5,662.0 pg·hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC).
Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol.
In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.
Pharmacodynamics: To confirm that systemic absorption does not play a role in the clinical response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled and oral fluticasone propionate was conducted. Doses of 100 and 500 mcg twice daily of fluticasone propionate inhalation powder were compared to oral fluticasone propionate, 20,000 mcg given once daily, and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled fluticasone propionate were effective in maintaining asthma stability and improving lung function while oral fluticasone propionate and placebo were ineffective. This demonstrates that the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not to an indirect effect through systemic absorption.
The potential systemic effects of inhaled fluticasone propionate on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at doses of 220, 440, 660, or 880 mcg twice daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For most patients, the ability to increase cortisol production in response to stress, as assessed by 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. No patient had an abnormal response (peak less than 18 mcg/dL) after dosing with placebo or 220 mcg twice daily. Ten percent (10%) to 16% of patients treated with fluticasone propionate at doses of 440 mcg or more twice daily had an abnormal response as compared to 29% of patients treated with prednisone.
Double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,818 adolescent and adult patients with asthma to assess the efficacy and/or safety of FLOVENT Inhalation Aerosol in the treatment of asthma. Fixed doses ranging from 22 to 880 mcg twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients with asthma included in these studies were those not adequately controlled with beta-agonists alone, those already maintained on daily inhaled corticosteroids, and those requiring oral corticosteroid therapy. In all efficacy trials, at all doses, measures of pulmonary function (forced expiratory volume in 1 second [FEV1] and morning peak expiratory flow [AM PEF]) were statistically significantly improved as compared with placebo.
In 2 clinical trials of 660 patients with asthma inadequately controlled on bronchodilators alone, FLOVENT Inhalation Aerosol was evaluated at doses of 44 and 88 mcg twice daily. Both doses of FLOVENT Inhalation Aerosol improved asthma control significantly as compared with placebo.
Figure 1 displays results of pulmonary function tests for the recommended starting dosage of FLOVENT Inhalation Aerosol (88 mcg twice daily) and placebo from a 12-week trial in patients with asthma inadequately controlled on bronchodilators alone. Because this trial used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint, which is the last evaluable FEV1 result and includes most patients' lung function data, are also provided. Pulmonary function improved significantly with FLOVENT Inhalation Aerosol compared with placebo by the second week of treatment, and this improvement was maintained over the duration of the trial.
In clinical trials of 924 patients with asthma already receiving daily inhaled corticosteroid therapy (doses of at least 336 mcg/day of beclomethasone dipropionate) in addition to as-needed albuterol and theophylline (46% of all patients), 22- to 440-mcg twice-daily doses of FLOVENT Inhalation Aerosol were also evaluated. All doses of FLOVENT Inhalation Aerosol were efficacious when compared to placebo on major endpoints including lung function and symptom scores. Patients treated with FLOVENT Inhalation Aerosol were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and patient-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma).
Figure 2 displays results of pulmonary function from a 12-week clinical trial in patients with asthma already receiving daily inhaled corticosteroid therapy (beclomethasone dipropionate 336 to 672 mcg/day). The mean percent change from baseline in lung function results for FLOVENT Inhalation Aerosol dosages of 88, 220, and 440 mcg twice daily and placebo are shown over the 12-week trial. Because this trial also used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint are included. Pulmonary function improved significantly with FLOVENT Inhalation Aerosol compared with placebo by the first week of treatment, and the improvement was maintained over the duration of the trial. Analysis of the endpoint results that adjusted for differential withdrawal rates indicated that pulmonary function significantly improved with FLOVENT Inhalation Aerosol compared with placebo treatment. Similar improvements in lung function were
seen in the other 2 trials in patients treated with inhaled corticosteroids at baseline.
In a clinical trial of 96 patients with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 10 mg), twice-daily doses of 660 and 880 mcg of FLOVENT Inhalation Aerosol were evaluated. Both doses enabled a statistically significantly larger percentage of patients to wean successfully from oral prednisone as compared with placebo (69% of the patients on 660 mcg twice daily and 88% of the patients on 880 mcg twice daily as compared with 3% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with FLOVENT Inhalation Aerosol had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.