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In patients with asthma, fluticasone furoate (FF) may provide greater protection against airway hyperresponsiveness, with less systemic activity and a wider therapeutic index (TI, or systemic activity/airway potency ratio), compared with fluticasone propionate (FP) and budesonide (BUD), according to study results published in the British Journal of Clinical Pharmacology.
Investigators conducted a dose-escalating, placebo-controlled, crossover, randomized study (ClinicalTrials.gov Identifier: NCT02991859) at 2 clinical research centers in the United Kingdom and 1 center in Germany. The researchers sought to compare the airway potency, systemic activity, and TI of 3 inhaled corticosteroids (ICS) — FF, FP, and BUD — that differ in their glucocorticoid receptor binding affinity, as well as their physicochemical and pharmacokinetic properties. Adult patients with asthma were randomly assigned to 1 of 2 treatment periods, with ≥25-days’ washout in between.
Each of the treatment periods comprised five 7-day dose-escalations or placebo:
1) FF: 25 µg/d to100 µg/d to 200 µg/d to 400 µg/d to 800 µg/d;
2) FP: 50 µg/d to 200 µg/d to 500 µg/d to1000 µg/d to 2000 µg/d;
3) BUD: 100 µg/d to400 µg/d to 800 µg/d to 1600 µg/d to 3200 µg/d.
On day 8, airway hyperresponsiveness to adenosine-5′ monophosphate (AMP PC20) was evaluated. Further, plasma cortisol was evaluated on day 1 (ie, predose baseline), as well as from pre-evening dose on day 6 to pre-evening dose on day 7 (ie, 24-hour weighted mean).
Between February 9, 2017, and December 20, 2018, a total of 54 participants were randomly assigned to treatment, with 26 individuals consenting to 1 treatment period and 28 individuals consenting to 2 treatment periods. All participants were between aged 18 and 65 years. The mean patient age was 37.9±13.96 years; 76% (41 of 54) of the participants were men. All of the patients had a history of bronchial asthma that had been diagnosed ≥6 months prior to screening. The study participants needed to demonstrate a prebronchial forced expiratory volume in 1 second (FEV1) ≥65% predicted at screening and to have documented sensitivity to AMP resulting in a decrease of ≥20% in FEV1 (ie, AMP PC20) of ≤80 mg/mL at screening.
Study results showed that treatment with FF was associated with greater airway potency than treatment with FP or BUD (AMP PC20 ED50 values of 48.52 µg/d, 1081.27 µg/d, and 1467.36 µg/d, respectively). Systemic activity — that is, cortisol suppression — ED50 values were 899.99 µg/d, 1986.05 µg/d, and 1927.42 µg/d, respectively.
The TI — that is, ED50 cortisol suppression/ED50 AMP PC20) — was considerably wider with FF (18.55) than with FP (1.84) or BUD (1.31). This was still apparent even when the ED50 for efficacy was measured using only the last administered PM dose, which yielded TI values for FP of 3.67 and for BUD of 2.63, which were still much lower than the FF values of 18.55.
Additionally, FF 100-µg/d and FF 200-µg/d doses were both comparable, with respect to airway potency, with high doses of FP ≥(ie, ≥1000 µg twice daily) and BUD (ie, ≥1500 µg twice daily). The systemic activity of FF 100 µg/d and FF 200 µg/d — that is, cortisol suppression of 7.41% and 14.28%, respectively — was comparable with low doses of FP (100 µg twice daily and 250 µg twice daily) and of BUD (100 µg twice daily and 200 µg twice daily).
The investigators concluded that the findings imply that all ICS are not therapeutically similar and, thus, may differ in TI. These results are relevant to asthma treatment guidelines, which currently assume that no difference in TI exists between ICS molecules.
Disclosure: This clinical trial was supported by GlaxoSmithKline. Please see the original reference for a full list of authors’ disclosures.
Reference
Daley-Yates P, Brealey N, Thomas S, e al. Therapeutic index of inhaled corticosteroids in asthma: a dose-response comparison on airway hyperresponsiveness and adrenal axis suppression [published online June 2, 2020]. Br J Clin Pharmacol. doi: 10.1111/bcp.14406
