A DOSE-RESPONSE STUDY COMPARING SUPPRESSION OF PLASMA-CORTISOL INDUCED BY FLUTICASONE PROPIONATE FROM DISKHALER AND BUDESONIDE FROM TURBUHALER

Objective: To compare the systemic potency of inhaled fluticasone prop ionate delivered via Diskhaler(R) (FP-DH), and inhaled budesonide deli vered via Turbuhaler(R) (BUD-TBH) over the clinically recommended dose range using plasma cortisol suppression as a marker for systemic acti vity. Methods: The systemic potency was examined in a dose-response st udy in 81 healthy male volunteers. The study was of an open, randomize d, parallel-group (four groups) design, where two treatments were give n in crossover fashion within each group. FP-DH and BUD-TBH were given b.i.d. for 7 days (14 doses): 100 and 100 mu g (group 1); 200 and 200 mu g (group 2); 500 and 400 mu g (group 3); 1000 and 800 mu g (group 4). There was a washout period of 7 days within each treatment group. All doses were administered at 08:00 and 20:00 hours. Multiple plasma cortisol samples were taken every 2 h over 24-h periods prior to rando mization (baseline) and during steady state (i.e., the last two dosing intervals). Cortisol suppression was determined by comparing average plasma concentrations of cortisol before and during treatment. Dose-re sponse curves for cortisol suppression were analyzed using multivariat e non-linear regression (Hill modeling). Results: Multiple dosing for 7 days with FP-DH and BUD-TBH resulted in dose-dependent cortisol supp ression by both drugs, most pronounced at the two highest dose levels. FP-DH-induced suppression was 41% at 500 mu g and 86% at 1000 mu g b. i.d., while that induced by BUD-TBH was 19% at 400 mu g and 47% at 800 mu g: b.i.d. Statistically significant differences were found when co mparing the two steroids at these two dose levels. Doses producing 50% of maximum suppression (ED50) were estimated at 833 mu g b.i.d. for B UD-TBH and 479 mu g b.i.d. for FP-DH. This gave an estimated relative cortisol suppression over the dose range of 1.74:1 (FP-DH:BUD-TBH). ED 50 values, estimated from cortisol concentrations at 08:00 hours (12 h after the last dose), were 1212 mu g b.i.d. for BUD-TBH and 527 mu g b.i.d. for FP-DH giving a relative cortisol suppression of 2.30:1 (FP- DH:BUD-TBH). Fourteen subjects on the highest FP-DH dose and 3 at the next highest dose had morning plasma cortisol levels below the lower r eference limit. No subject taking budesonide, however, had morning pla sma cortisol levels below the reference limit. Analysis of the time fo r return to pretreatment baseline levels showed that cortisol suppress ion, 12-24 h after the last dose, was statistically significant compar ed with the baseline for the highest dose of FP-DH but not for any of the BUD-TBH doses. Conclusions: The results of the present study show that FP-DH suppresses plasma cortisol more than BUD-TBH on a equivalen t basis with regard to both magnitude and duration.