Evaluation of the administration time effect on the cumulative cortisol suppression and cumulative lymphocytes suppression for once-daily inhaled corticosteroids: a population modeling/simulation approach.

Inhaled glucocorticoids continue to be first-line therapy in asthma. To improve improving patient compliance, newer inhaled glucocorticoids have been developed for once-a-day treatment. This study was interested in identifying the optimal time of dosing using 2 surrogate markers of glucocorticoid action. A previously published study on the pharmacokinetics and pharmacodynamics (cortisol and blood lymphocyte suppression) of the inhaled glucocorticoids budesonide and fluticasone propionate was reanalyzed using a population pharmacokinetic approach. A stochastic numerical simulation using NONMEM assessed the effects of time of dosing on cortisol (side effect parameter) and blood lymphocytes (side effect and effect parameter). The effects on cortisol were more pronounced when the glucocorticoids were given in the morning, whereas the effects on lymphocytes (an effect controlled by endogenous and exogenous glucocorticoids) were maximized when dosing occurred in the late afternoon or evening. Twice-daily dosing of the same dose resulted in smaller differences between maximum and minimal effects. These were of no clinical relevance. Simulations for once-daily dosing support clinical studies that reported a higher antiasthmatic effect and lower cortisol suppression when once-daily dosing occurs in the evening.