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).

Phenotype-Guided Asthma Therapy: An Alternative Approach to Guidelines

“…In contrast, a pharmacological study concluded that ICS molecules are not therapeutically similar: across the approved doses for asthma, fluticasone furoate (FF) gave more protection against airway hyperresponsiveness with less systemic activity (measured via 24-hour plasma cortisol suppression), and had a wider therapeutic index (systemic activity/airway potency ratio), than FP or budesonide. 61 On the other hand, when we look at GINA steps 3 to 5, we can see that ICS/formoterol is preferred over SABA as rescue medication. However, this might be a problem in patients who are receiving other combinations such as FF/ vilanterol because we don't have any experience in using two different combinations simultaneously in the same patient.…”

End‐point selection to determine the airway‐systemic ratio of inhaled corticosteroids in asthma

“…We read with interest the study by Daley-Yates et al 1 given that we already know that FF suppresses an ICS responsive type 2 biomarker, namely fractional exhaled nitric oxide (FeNO), for 18 days after cessation. 4 This in turn would result in an appreciable carryover effect of FF between weekly dose escalation which would not be seen with BUD as this has much shorter lung retention, and would further confound meaningful interpretation of any doseresponse effect.…”

“…We read with interest the study by Daley-Yates et al 1 which evaluated the relative therapeutic index of budesonide (BUD), fluticasone propionate (FP) and fluticasone furoate (FP) in asthma patients. We believe there are several inherent flaws with the design methodology of the trial which limit the clinical validity of the results.…”

Direct and indirect bronchoprovocation tests in dose‐response studies of inhaled corticosteroids: Past, present, and future directions

“…Only one AMP challenge study reported a significant DR with FP in a recent incomplete crossover, 2‐period, dose‐escalation trial. 26 The FP dose‐escalation arm involved sequential doses: 50, 200, 500, 1,000, and 2,000 mcg/d. The dose‐shifts were 0, 0.4, 1.1, 1.7, and 2.3, respectively.…”

“…One AMP challenge study included a fluticasone furoate (FF) dose‐escalation arm at sequential doses of 25, 100, 200, 400, and 800 mcg/d 26 . Dose‐shifts in AMP PC 20 from baseline were 1.1, 2.4, 2.9, 3.3, and 3.5, respectively, which suggests that the DR develops a plateau.…”