DYNAMIC MODELING OF CORTISOL REDUCTION AFTER INHALED ADMINISTRATION OF FLUTICASONE PROPIONATE

Fluticasone propionate (FP) is a new corticosteroid that has been deve loped for the treatment of asthma, The compound has a very high recept or affinity, 18 times that of dexamethasone. After inhalation, FP is s ystemically available because of inhaled bioavailability. In healthy s ubjects 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-mu g, 1,000-mu g, and 2,000-mu g doses of FP. Blood samples were collected over a 24-hour period after administration, Concentrations o f FP and cortisol were measured in plasma by immunoassay. Cortisol red uction was chosen as the pharmacodynamic parameter. A novel linear rel ease rate model was used to parameterize the cortisol data, The pharma cokinetics of FP were linear over the dose range studied, The cortisol release parameters were determined from baseline data (before drug ad ministration), Based on these results, the E(50) values for cortisol r eduction were then determined for each dose of FP. The overage E(50) w as 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 vi vo pharmacodynamic values measured in healthy subjects are in good agr eement with the relatively high receptor affinity of FP.