Advair Diskus - Clinical Pharmacology

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In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3 ,5 -adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung.

Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.

Pharmacokinetics:

ADVAIR DISKUS:

Following administration of ADVAIR DISKUS to healthy subjects, peak plasma concentrations of fluticasone propionate were achieved in 1 to 2 hours and those of salmeterol were achieved in about 5 minutes. In a single-dose crossover study, a higher than recommended dose of ADVAIR DISKUS was administered to 14 healthy subjects.

Two (2) inhalations of the following treatments were administered:

ADVAIR DISKUS 500/50, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, and fluticasone propionate powder 500 mcg alone. Mean peak plasma concentrations of fluticasone propionate averaged 107, 94, and 120 pg/mL, respectively, and of salmeterol averaged 200 and 150 pg/mL, respectively, indicating no significant changes in systemic exposures of fluticasone propionate and salmeterol. In a repeat-dose study, the highest recommended dose of ADVAIR DISKUS was administered to 45 patients with asthma.