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Abstract

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.

Exposure-Response and Clinical Outcome Modeling of Inhaled Budesonide/Formoterol Combination in Asthma Patients

“…It is often difficult to quantify the CO and therefore CO has been rarely used in quantitative modeling and simulations [47]. Accordingly, there have been a number of studies which investigated the PK/PD relationship for inhaled drugs, but models that describe the PK/PD/CO relationship are not common [22,23,[48][49][50]. In this study, the ACT, a quantitative method of evaluating CO for control of asthma, was utilized, and therefore we were able to establish the PK/PD/CO relationships for budesonide and formoterol.…”

Systemic exposure to fluticasone MDI delivered through antistatic chambers

“…In adults, the plasma concentration of FP producing a 50 % decrease in maximal cortisol secretion (EC 50 ) was 100 pg/mL in one study[9] and 130 pg/ML in another[10]. The corresponding value for children is unknown.…”

Review in Pharmacokinetic Models on Corticosteroids

“…A two-compartment model was applied after a single oral administration of prednisolone [53,54], and after inhaled flunisolide [55], which showed a biexponential decreasing phase after a peak. Flunisolide is a synthetic corticosteroid which is inhaled in the treatment of asthma.…”

“…Circadian variations of plasma hydrocortisone concentrations showing an asymetric profile[20,55,77].…”