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

Abstract

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 (μg/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 PC₂₀ dose at which 50% of the maximum effect is achieved [ED₅₀ ] values: 48.52, 1081.27 and 1467.36 μg/d, respectively). Systemic activity (cortisol suppression) ED₅₀ values were 899.99, 1986.05 and 1927.42 μg/d, respectively. The therapeutic index (ED₅₀ cortisol suppression/ED₅₀ AMP PC₂₀ ) was wider for FF (18.55) than FP (1.84) and BUD (1.31). FF 100 μg/d and 200 μg/d were both comparable in terms of airway potency with high doses of FP (≥1000 μg twice daily [BID]) and BUD (≥1500 μg/BID). The systemic activity of FF 100 μg/d and 200 μg/d (cortisol suppression: 7.41% and 14.28%, respectively) was comparable with low doses of FP (100 μg/BID and 250 μg/BID) and BUD (100 μg/BID and 200 μg/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).

Keywords: AMP challenge; asthma; budesonide; fluticasone furoate; fluticasone propionate; therapeutic index.

FIGURE 1

Subject flow through the study. Note: dose refers to total daily dose of the relevant treatment. ^aReasons for screening failure were not mutually exclusive; subjects could have more than 1 reason for exclusion at the screening stage. ^bOne subject withdrew during treatment period 1, FP 50 μg. ^cOne subject withdrew during treatment period 1, FF 25 μg. ^dOne subject withdrew during treatment period 1, FP 500 μg; a second subject completed treatment period 1, FP 500 μg, but withdrew from the study before entering FP 1000 μg. ^eOne subject withdrew during treatment period 1, FF 200 μg. ^fOne subject withdrew during treatment period 2, placebo 4; another subject did not enter treatment period 1, placebo 5, but was not withdrawn from the study and continued into treatment period 2. ^gOne subject completed treatment period 2, FF 800 μg, but withdrew from the study before completing final study assessments. ^hTwo subjects completed treatment period 1 (placebo 5 and FP 2000 μg, respectively), but withdrew during the washout period before entering treatment period 2. BUD = budesonide; FF = fluticasone furoate; FP = fluticasone propionate

FIGURE 2

Airway potency (AMP PC₂₀) and systemic activity (0–24 h weighted mean plasma cortisol suppression) by total daily dose and treatment (pharmacodynamic population). Note: Estimates and 95% CIs for AMP PC₂₀ were obtained on the log₂ scale and back‐transformed. Error bars represent the 95% CIs. AMP PC₂₀ = provocative concentration of adenosine‐5′‐monophosphate causing a ≥20% decline in forced expiratory volume in 1 second; BUD = budesonide; CI = confidence interval; FF = fluticasone furoate; FP = fluticasone propionate; ICS = inhaled corticosteroid

FIGURE 3

Comparison of airway potency and systemic activity by total daily dose of FF, FP and BUD (pharmacodynamic population). Note: The horizontal dashed reference line represents the cut‐off for high‐dose ICS, as defined by GINA (FP >500 μg/d and BUD >800 μg/d). The vertical dashed line is a reference point for a low level of plasma cortisol suppression (20% or ED₂₀ for cortisol suppression, as estimated in this study). AMP PC₂₀ = provocative concentration of adenosine‐5′‐monophosphate causing a ≥20% decline in forced expiratory volume in 1 second; BUD = budesonide; ED₂₀ = dose at which 20% of the maximum effect is reached; FF = fluticasone furoate; FP = fluticasone propionate; GINA = Global Initiative for Asthma; ICS = inhaled corticosteroid