Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate

What is already known about this subject • Mometasone furoate (MF) is a new inhaled glucocorticoid for which the first reports suggested a low degree of systemic side‐effects and low systemic availability. • Recent studies of Fardon and colleagues have shown that MF's cortisol suppression is similar to that of fluticasone. • Pharmacokinetic/dynamic evaluations of MF's systemic side‐effects, probing whether systemic side‐effects can be explained by systemic availability, plasma protein binding and receptor binding affinity, are lacking in the literature. What this study adds • This study shows that the systemic availability of MF and fluticasone propionate (FP) are similar and that systemic availability is directly related to the dose. • It also shows that the metabolites of MF are present only in very low concentrations at most, contrary to results in rats. • The observed cortisol suppression of FP and MF is related to the trough plasma concentrations and seems to be in agreement with its observed systemic availability, plasma protein binding and receptor binding affinity. Aim Fluticasone propionate (FP) and mometasone furoate (MF) are inhaled corticosteroids that possess a high ratio of topical to systemic activity. The systemic bioavailability of MF has been claimed to be minimal (1%). FP has been shown to exhibit the same degree of systemic effects, but its systemic availability is between 13 and 17%. We hypothesize that FP and MF have comparable systemic availabilities that can explain their potential to cause systemic effects. Methods Steady‐state FP and MF trough plasma samples were determined from a clinical study by Fardon et al. in patients with persistent asthma (forced expiratory volume in 1 s = 91%). The percent plasma protein binding of FP and MF was measured using ultracentrifugation. Free FP plasma concentrations were normalized for their differences in receptor binding affinity compared with MF and linked to overnight urinary cortisol/creatinine with an inhibitory Emax. Results A plot of steady‐state FP and MF total trough plasma concentrations vs. dose showed that both drugs exhibit dose linearity. MF has comparable bioavailability to FP based on the steady‐state concentrations observed for the different doses. The free plasma concentration producing 50% of urinary cortisol suppression (IC50) for MF was not statistically different from the free, normalized IC50 for FP. Conclusion FP and MF have similar pulmonary deposition and the same potential to cause systemic side‐effects due to their similar IC50 values. The observed urinary cortisol suppression of FP and MF is in agreement with their systemic availability, their differences in plasma protein binding and receptor binding affinity.