The Relationship Between Fluticasone Furoate Systemic Exposure and Cortisol Suppression

INTRODUCTION: The inhaled corticosteroid (ICS) fluticasone furoate is in development, in combination with the long-acting beta(2)-agonist vilanterol for the once-daily treatment of asthma and chronic obstructive pulmonary disease and as a monotherapy treatment for asthma. Corticosteroids, including ICSs, have the potential to induce dose-dependent systemic effects on the hypothalamic–pituitary–adrenal (HPA) axis. Cortisol suppression has been observed in asthma patients with normal HPA axis function at baseline on receiving high doses of ICSs, and is associated with adverse effects on a number of physiological processes. The measurement of 24-h serum cortisol and 24-h urinary cortisol excretion are sensitive methods for assessing adrenocortical activity, and can evaluate cortisol suppression in a dose-dependent manner. OBJECTIVE: The purpose of the meta-analysis presented here was to characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure [as measured by area under the concentration–time curve over 24 h postdose (AUC(24))] and both 24-h weighted mean serum cortisol (WM24) and 24-h urine cortisol excretion in healthy subjects and subjects with asthma. METHODS: The serum cortisol meta-analysis integrated eight studies; five Phase I studies in healthy subjects, two Phase IIa studies, and one Phase III study in subjects with asthma. Each study included serial blood sampling for estimation of WM24. The urine cortisol meta-analysis integrated three studies: one Phase I study in healthy subjects, and one Phase IIb and one Phase III study in subjects with asthma. Each study included complete 0–24 h urine collection for estimation of urine cortisol excretion. All studies included blood sampling for estimation of fluticasone furoate AUC(24). A sigmoid maximum effect (E (max)) model was fitted to fluticasone furoate AUC(24) and serum cortisol and urine cortisol data using nonlinear mixed-effect modeling with the computer program NONMEM(®). RESULTS: Over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range, the relationship between fluticasone furoate AUC(24) and WM24 and 24-h urine cortisol excretion was well described by an E (max) model. The average estimate of AUC producing 50 % of maximum effect (AUC(50)) was similar for the serum cortisol and urine cortisol models with values of 1,556 and 1,686 pg·h/mL, respectively. Although formulation/inhaler was shown to be a significant covariate on the estimates of both WM24 at zero concentration (C(0)) and AUC(50) in the serum cortisol model, the differences were small and believed to be due to study variability. Age was shown to be a significant covariate on the estimates of both C (0) and AUC(50) in the urine cortisol model, and was considered to be a reflection of lower urine cortisol excretion in adolescents. CONCLUSION: A pharmacokinetic/pharmacodynamic model has been established over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range to both WM24 and 24-h urine cortisol excretion. The values of AUC(50) of 1,556 and 1,686 pg·h/mL, respectively, are several times higher than average fluticasone furoate AUC(24) values observed at clinical doses of fluticasone furoate (≤200 μg). The models predict a fluticasone furoate AUC(24) of 1,000 pg·h/mL would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17 %, respectively.