Dynamic Modeling of Cortisol Reduction after Inhaled Administration of Fluticasone Propionate

Abstract

Fluticasone propionate (FP) is a new corticosteroid that has been developed for the treatment of asthma. The compound has a very high receptor affinity, 18 times that of dexamethasone. After inhalation, FP is systemically available because of inhaled bioavailability. In healthy subjects this may lead to measurable systemic effects, such as cortisol reduction. A clinical study was conducted in 12 healthy volunteers to determine the systemic effects after inhaled administration of single 500-μg, 1,000-μg, and 2,000-μg doses of FP. Blood samples were collected over a 24-hour period after administration. Concentrations of FP and cortisol were measured in plasma by immunoassay. Cortisol reduction was chosen as the pharmacodynamic parameter. A novel linear release rate model was used to parameterize the cortisol data. The pharmacokinetics of FP were linear over the dose range studied. The cortisol release parameters were determined from baseline data (before drug administration). Based on these results, the E₅₀ values for cortisol reduction were then determined for each dose of FP. The average E₅₀ was 0.134 ng/mL for total FP concentrations and 0.013 ng/mL for unbound FP concentrations; these results were not dose dependent. These in vivo pharmacodynamic values measured in healthy subjects are in good agreement with the relatively high receptor affinity of FP.