Pharmacokinetic/pharmacodynamic modeling of cortisol suppression after oral administration of fluocortolone.

Fluocortolone is a potent corticosteroid used orally for the treatment of rheumatic diseases, asthma, and immunosuppression. A clinical study of nine healthy volunteers was conducted to determine the pharmacokinetics and cortisol suppression after administration of single oral doses of 20 mg, 50 mg, and 100 mg of fluocortolone. Blood samples were collected at 8:00 AM, 12:00 PM, and 4:00 PM on the day before treatment, and 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 28, 32, 48, 52, and 56 hours after administration of the drug. Concentrations of fluocortolone and cortisol were measured in plasma by a reversed phase high-performance liquid chromatography system. Cortisol suppression was chosen as the pharmacodynamic parameter. Total concentrations were converted into unbound concentrations using a two-protein, one-ligand equation. The unbound concentrations were fitted using a one-compartment body model equation with first-order absorption. A linear release-rate model was used to characterize the cortisol data. The data were fitted using a common E50 value of 0.95 +/- 0.22 ng/mL for the mean data. The value of E50 was in close agreement with the prediction based on relative glucocorticoid receptor affinity.