Daley-Yates Peter, Brealey Noushin, Thomas Sebin, Austin Daren, Shabbir Shaila, Harrison Tim, Singh Dave, Barnes Neil
Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline plc, Uxbridge, UK.
Biostatistics and Programming, GlaxoSmithKline plc, Bangalore, India.
Br J Clin Pharmacol. 2021 Feb;87(2):483-493. doi: 10.1111/bcp.14406. Epub 2020 Jun 17.
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.
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 PC ) 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).
Fifty-four subjects were randomised. FF showed greater airway potency than FP and BUD (AMP PC dose at which 50% of the maximum effect is achieved [ED ] values: 48.52, 1081.27 and 1467.36 μg/d, respectively). Systemic activity (cortisol suppression) ED values were 899.99, 1986.05 and 1927.42 μg/d, respectively. The therapeutic index (ED cortisol suppression/ED AMP PC ) 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).
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).
比较三种吸入性糖皮质激素的气道效能、全身活性和治疗指数，这三种激素在糖皮质激素受体结合亲和力、理化性质和药代动力学特性方面存在差异。
本递增剂量、安慰剂对照、交叉研究将成年哮喘患者随机分为1个或2个治疗期，期间有≥25天的洗脱期。每个治疗期包括五个7天的剂量递增（μg/天）：糠酸氟替卡松（FF；25→100→200→400→800）、丙酸氟替卡松（FP；50→200→500→1000→2000）、布地奈德（BUD；100→400→800→1600→3200）或安慰剂。在第8天评估对5'-单磷酸腺苷（AMP PC）的气道高反应性。在第1天（给药前基线）以及从第6天的下午给药前至第7天的下午给药前（24小时加权平均值）评估血浆皮质醇。
54名受试者被随机分组。FF显示出比FP和BUD更高的气道效能（达到最大效应50%时的AMP PC剂量[ED]值：分别为48.52、1081.27和1467.36μg/天）。全身活性（皮质醇抑制）的ED值分别为899.99、1986.05和1927.42μg/天。FF的治疗指数（ED皮质醇抑制/ED AMP PC）（18.55）比FP（1.84）和BUD（1.31）更宽。FF 100μg/天和200μg/天在气道效能方面与高剂量的FP（≥1000μg，每日两次[BID]）和BUD（≥1500μg/BID）相当。FF 100μg/天和200μg/天的全身活性（皮质醇抑制：分别为7.41%和14.28%）与低剂量的FP（100μg/BID和250μg/BID）和BUD（100μg/BID和200μg/BID）相当。
本研究提供的证据表明，与FP或BUD相比，FF能提供更多针对气道高反应性的保护，且全身活性更低。这表明并非所有吸入性糖皮质激素在治疗上都相似，它们的治疗指数可能存在差异。（203162；NCT02991859）
