icasone propionate was negligible (<1%), primarily due toincomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majorityof the fluticasone propionate delivered to the lung was systemically absorbed.
After administration of 232/14 mcg fluticasone propionate/salmeterol MDPI to patients aged 12years and older with persistent asthma in a clinical trial, the mean Cmax value of fluticasonepropionate was 66 pg/mL with a median tmax value of approximately 2 hours.
Salmeterol:
After administration of 232/14 mcg fluticasone propionate/salmeterol MDPI to patients aged 12years and older with persistent asthma, the mean Cmax values of salmeterol was 60 pg/mL. Themedian tmax was 5 minutes.
Distribution
Fluticasone Propionate:
Following intravenous administration, the initial disposition phase for fluticasone propionate wasrapid and consistent with its high lipid solubility and tissue binding. The volume of distributionaveraged 4.2 L/kg.
The percentage of fluticasone propionate bound to human plasma proteins averages 99%.
Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantlybound to human transcortin.
Salmeterol:
Volume of distribution data are not available for salmeterol.
The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over theconcentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrationsthan those achieved following therapeutic doses of salmeterol.
Elimination
Fluticasone Propionate:
Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had aterminal elimination half-life of approximately 7.8 hours. Terminal half-life estimates offluticasone propionate following oral inhalation administration of fluticasonepropionate/salmeterol MDPI were approximately 10.8 hours.
Metabolism
The total clearance of fluticasone propionate is high (average, 1,093 mL/minute), with renalclearance accounting for less than 0.02% of the total. The only circulating metabolitedetected in humans is the 17β carboxylic acid derivative of fluticasone propionate, which isformed through the CYP3A4 pathway. This metabolite has less affinity (approximately1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitroand negligible pharmacological activity in animal studies. Other metabolites detected in vitrousing cultured human hepatoma cells have not been detected in humans.
Excretion
Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with theremainder excreted in the feces as parent drug and metabolites.
Salmeterol:
Terminal half-life estimates for salmeterol for fluticasone propionate/salmeterol MDPI wereapproximately 12.6 hours.
The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highlyprotein bound (greater than 99%) and has a long elimination half-life of 11 days.
Metabolism
Salmeterol base is extensively metabolized by hydroxylation.
An in vitro study using human liver microsomes showed that salmeterol is extensivelymetabolized to α hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, astrong inhibitor of CYP3A4, essentially completely inhibited the formation of αhydroxysalmeterol in vitro.
Excretion
In 2 healthy adult subjects who received 1 |
