Dependency of Cortisol Suppression on the Administration Time of Inhaled Corticosteroids

Abstract

Endogenous cortisol suppression is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. A previously developed pharmacokinetic/ pharmacodynamic approach was used to evaluate the influence of administration time on the cumulative cortisol suppression (CCS) after single doses of the inhaled corticosteroids flunisolide and fluticasone propionate. Administration time-dependent simulations of CCS were performed with drug-specific pharmacokinetic and pharmacodynamic parameters obtained from previous clinical trials. Both drugs showed similar diurnal variation in CCS, dependent on the administration time, with maximum suppression when administered in the early morning at approximately 3 AM. The optimum administration time for minimized CCS was in the afternoon but was shifted from 3 PM for fluticasone propionate to later time points around 7 PM for flunisolide, probably because of the shorter terminal elimination half-life of flunisolide. Regarding peak to trough fluctuation, however, CCS after fluticasone 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-dependent variations. This led to the conclusion that administration time has to be considered as a pivotal influential factor in clinical studies comparing CCS among different inhaled corticosteroids.

Modeling Circadian Rhythms of Glucocorticoid Receptor and Glutamine Synthetase Expression in Rat Skeletal Muscle

“…Circadian rhythms elicit changes in sensitivity of response, depending on the timing of drug administration. Studies of the biological rhythm of human plasma cortisol suggest that cortisol suppression by inhaled corticosteroids is at maximum when administered at 3 a.m. and minimized when injected in the afternoon (24). Dexamethasone injected prior to the zenith results in prolonged and/or stronger expression of its downstream gene in mice, whereas the same treatment induces a new surge of gene expression if injected after the peak time (4).…”

Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening

“…Concerning safety, pharmacokinetic/pharmacodynamic modelling suggests that inhalation of steroids in the afternoon might cause the least cortisol suppression, with the optimum time point being determined by the terminal elimination half-life of the respective drug: i.e. an administration time point of 15:00 h was proposed for fluticasone propionate and of 19:00 h for flunisolide [14]. Finally, due to the circadian rhythm in lung function, hyperresponsiveness, circulating cells and mediators in asthma, it might be expected that based on the results with oral and intravenous steroids [15,16], afternoon/evening dosing of inhaled steroids is preferable to morning dosing for alleviation of nocturnal worsening in asthma.…”

A Review on the Safety and Efficacy of Inhaled Corticosteroids in the Management of Asthma

“…The extent of suppression is dependent on the dose, duration, and timing of ICS administration [94][95][96][97][98]. In adults, HPA suppression appears to occur at doses above 800 lg/day BDP equivalent [99].…”