DEPENDENCY OF CORTISOL SUPPRESSION ON THE ADMINISTRATION TIME OF INHALED CORTICOSTEROIDS

Endogenous cortisol suppression is one of the major systemic side effe cts of inhaled corticosteroids in the treatment of asthma. A previousl y developed pharmacokinetic/pharmacodynamic approach ws used to evalua te the influence of administration time on the cumulative cortisol sup pression (CCS) after single doses of the inhaled corticosteroids fluni solide and fluticasone propionate. Administration time-dependent simul ations of CCS were performed with drug-specific pharmacokinetic and ph armacodynamic parameters obtained from previous clinical trials. Both drugs showed similar diurnal variation in CCS, dependent on the admini stration time, with maximum suppression when administered in the early morning at approximately 3 AM. The optimum administration time for mi nimized CCS was in the afternoon but was shifted from 3 PM for flutica sone propionate to later time points around 7 PM for flunisolide, prob ably because of the shorter terminal elimination half-life of flunisol ide. Regarding peak to trough fluctuation, however, CCS after fluticas one propionate showed only half the administration time dependency as after flunisolide. Therefore, the ratio between CCS after flunisolide and after fluticasone propionate also followed administration time-dep endent variations. This led to the conclusion that administration time has to be considered as a pivotal influential factor in clinical stud ies comparing CCS among different inhaled corticosteroids.