Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway hyperresponsiveness and adrenal axis suppression

Aims To compare the airway potency, systemic activity and therapeutic index of three inhaled corticosteroids that differ in glucocorticoid receptor binding affinity, physicochemical and pharmacokinetic properties. Methods This escalating-dose, placebo-controlled, cross-over study randomised adults with asthma to 1 or 2 treatment periods with >= 25 days washout in-between. Each treatment period comprised five 7-day dose escalations (mu g/d): fluticasone furoate (FF; 25 -> 100 -> 200 -> 400 -> 800), fluticasone propionate (FP; 50 -> 200 -> 500 -> 1000 -> 2000), budesonide (BUD; 100 -> 400 -> 800 -> 1600 -> 3200) or placebo. Airway hyperresponsiveness to adenosine-5'-monophosphate (AMP PC20) was assessed on day 8. Plasma cortisol was assessed on day 1 (predose baseline) and from pre-PM dose on day 6 to pre-PM dose day 7 (24-h weighted mean). Results Fifty-four subjects were randomised. FF showed greater airway potency than FP and BUD (AMP PC(20)dose at which 50% of the maximum effect is achieved [ED50] values: 48.52, 1081.27 and 1467.36 mu g/d, respectively). Systemic activity (cortisol suppression) ED(50)values were 899.99, 1986.05 and 1927.42 mu g/d, respectively. The therapeutic index (ED(50)cortisol suppression/ED(50)AMP PC20) was wider for FF (18.55) than FP (1.84) and BUD (1.31). FF 100 mu g/d and 200 mu g/d were both comparable in terms of airway potency with high doses of FP (>= 1000 mu g twice daily [BID]) and BUD (>= 1500 mu g/BID). The systemic activity of FF 100 mu g/d and 200 mu g/d (cortisol suppression: 7.41% and 14.28%, respectively) was comparable with low doses of FP (100 mu g/BID and 250 mu g/BID) and BUD (100 mu g/BID and 200 mu g/BID). Conclusion This study provides evidence that FF can provide more protection against airway hyperresponsiveness, with less systemic activity, than FP or BUD. This suggests that all inhaled corticosteroids are not therapeutically similar and may differ in their therapeutic index. (203162; NCT02991859).

Automated summary

This study compared the airway potency, systemic activity, and therapeutic index of three inhaled corticosteroids. Fluticasone furoate (FF) showed greater airway potency and less systemic activity compared to fluticasone propionate (FP) and budesonide (BUD), suggesting that FF may provide better protection against airway hyperresponsiveness with a wider therapeutic index.