Inhaled Fluticasone Propionate: A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Asthma

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Abstract

Synopsis

Fluticasone propionate is an androstane carbothioate glucocorticosteroid with almost twice the topical anti-inflammatory potency of beclomethasone dipropionate. Importantly, it is not appreciably absorbed from the gastrointestinal tract. However, the fraction of active drug absorbed from the lungs after inhalation, and therefore total systemic availability, has yet to be determined.

Synopsis

Inhaled fluticasone propionate administered at dosages of 1500 μg/day for 1 year or 2000 μg/day for 6 weeks did not cause clinically significant pituitary-adrenal suppression. Preliminary data from 2 published trials also indicate no significant effect on growth in children. However, wider clinical experience is needed to clarify the effects of long term administration on pituitary-adrenal function, bone metabolism and attainment of adult height in children.

Synopsis

In clinical studies, inhaled fluticasone propionate was at least as effective as beclomethasone dipropionate or budesonide when administered at half the dosage of the comparators in patients with mild to moderate or severe asthma. Limited data suggest that fluticasone propionate also has considerable potential in the management of childhood asthma. In trials of up to 1 year in duration, fluticasone propionate appeared to be well tolerated by both adults and children.

Synopsis

Whether an improved tolerability profile compared with other corticosteroids is a major clinical benefit of the extremely low oral bioavailability of inhaled fluticasone propionate requires confirmation. Nevertheless, on the basis of available data from initial clinical trials of mostly limited duration, inhaled fluticasone propionate offers an effective treatment option for the management of asthma, with the potential of an enhanced safety profile.

Pharmacological Properties

Relative topical vasoconstrictor potency values (arbitrary units) in humans were considerably greater for fluticasone propionate (945) than for fluocinolone acetonide (100) or beclomethasone dipropionate (50). In an animal model, an index of topical to systemic activity determined for fluticasone propionate (91) was superior to that for fluocinolone acetonide (1) and beclomethasone dipropionate (0.4).

Pharmacological Properties

In vitro, the affinity of fluticasone propinate for the glucocorticoid receptor of human lung cytosol exceeded that of budesonide, dexamethasone and flunisolide. Preliminary data suggest that long term fluticasone propionate therapy may reduce bronchial hyper-reactivity and airways inflammation.

Pharmacological Properties

Single-dose oral fluticasone propionate 16mg or intranasal fluticasone propionate 4000 μg/day administered for 7 days had no significant effect on mean morning plasma cortisol levels in healthy volunteers. Similarly, no significant reductions in morning plasma or serum cortisol levels were demonstrated in adult asthma patients treated with inhaled fluticasone propionate at dosages of 1500 μg/day for 1 year and 2000 μg/day for 6 weeks, or in asthmatic children administered dosages of 100 or 200 μg/day for up to 9 months. Furthermore, initial comparative studies suggest that inhaled fluticasone propionate may have less effect on pituitary-adrenal function in adult and paediatric patients, and growth of long bones in children, than beclomethasone dipropionate.

Pharmacological Properties

Systemic effects of inhaled corticosteroids are due to the absorption of active drug from the gastrointestinal and lower respiratory tracts. Preliminary pharmacokinetic data indicate that the oral bioavailability of fluticasone propionate is negligible. However, the fraction of unchanged drug absorbed from the lungs after inhalation has not been determined and thus the overall systemic availability of inhaled fluticasone propionate is unknown.

Therapeutic Efficacy

The efficacy of inhaled fluticasone propionate 50 to 2000 μg/day administered for up to 1 year has been assessed in more than 4000 patients with asthma.

Therapeutic Efficacy

In the treatment of mild to moderate asthma, inhaled fluticasone propionate 50 to 200 μg/day was more effective than placebo as shown by significant improvements in lung function and symptom scores, and reduced use of supplementary anti-asthmatic medication.

Therapeutic Efficacy

Comparisons with active agents have shown that fluticasone propionate 200 to 1000 μg/day is at least as effective as beclomethasone dipropionate 400 to 2000 μg/day in the treatment of asthma, including severe disease. Fluticasone propionate 200 and 1000 μg/day was significantly more effective than budesonide 400 and 1600 μg/day, respectively. In patients with moderate asthma, fluticasone propionate 500 μg/day was significantly more effective than nedocromil 16 mg/day. Fluticasone propionate 1500 or 2000 μg/day has also facilitated the discontinuation of oral prednisone in patients with severe asthma.

Therapeutic Efficacy

Limited data have demonstrated the usefulness of fluticasone propionate in the treatment of childhood asthma. Fluticasone propionate 200 μg/day was at least as effective as beclomethasone dipropionate 400 μg/day, while a dosage of 100 μg/day was significantly more effective than sodium cromoglycate 80 mg/day.

Tolerability

Clinical studies suggest that treatment with inhaled fluticasone propionate for up to 1 year is well tolerated by adults at dosages of up to 2000 μg/day and by paediatric patients at dosages of up to 200 μg/day. The most commonly reported adverse events included oral candidiasis, dysphonia and upper respiratory tract infection. However, data on longer term treatment are required, particularly in children.

Tolerability

Fluticasone propionate 100 to 1500 μg/day was as well tolerated as beclomethasone dipropionate 400 to 2000 μg/day, with both drugs producing a similar spectrum of local adverse events. Fluticasone propionate administered at dosages of 100, 500 and 2000 μg/day, respectively, demonstrated equivalent tolerability to sodium cromoglycate 80 mg/day, nedocromil 16 mg/day and budesonide 1600 μg/day.

Dosage and Administration

Twice-daily inhaled fluticasone propionate at total daily dosages of 50 to 2000μg has been used for the treatment of mild to severe asthma in adults, while dosages of 100 and 200 μg/day have been used in childhood asthma. Inhaled fluticasone propionate is available as metered dose aerosol and dry powder formulations.

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