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Pulm Pharmacol Ther. 2018 Jun;50:11-18. doi: 10.1016/j.pupt.2018.03.001. Epub 2018 Mar 13.
The budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) is an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination formulated with innovative co-suspension delivery technology that is in clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, Phase I, single-dose, six-treatment, four-period, crossover study (NCT01980615) examined the pharmacokinetic (PK) and safety profile of three doses of BGF MDI (320/14.4/10 μg [equivalent to budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 μg], 160/14.4/10 μg and 80/14.4/10 μg), two doses of a budesonide/formoterol fumarate dihydrate fixed-dose combination (BUD/FORM MDI 320/9 μg and 160/9 μg; not using co-suspension delivery technology) and a glycopyrronium/formoterol fumarate dihydrate co-suspension delivery technology MDI (GFF MDI 14.4/10 μg) in healthy volunteers (18-45 years of age). PK parameters included area under the plasma concentration-time curve from 0 to 12 h (AUC), AUC up to the last measurable concentration (AUC), maximum plasma concentration (C) and time to maximum plasma concentration (t). Safety was monitored throughout the study. Of 84 subjects randomized, 76 completed the study. BGF MDI 320/14.4/10 μg was bioequivalent to BUD/FORM MDI 320/9 μg for budesonide for C, AUC and AUC (primary objective). Dose proportionality was observed for the budesonide component between BGF MDI 80/14.4/10 μg and BGF MDI 160/14.4/10 μg, and between BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg. Systemic exposure to glycopyrronium and formoterol after BGF MDI 320/14.4/10 μg treatment was similar to GFF MDI 14.4/10 μg. The rate of adverse events was 3.7-17.9% across treatments without any serious adverse events. In conclusion, BGF MDI 320/14.4/10 μg had a similar budesonide PK profile to BUD/FORM MDI 320/9 μg. No PK drug-drug interactions were observed when budesonide was added to glycopyrronium and formoterol fumarate dihydrate. These data support the use of budesonide 320 μg and 160 μg in future clinical trials of BGF MDI in COPD.
布地奈德/格隆溴铵/福莫特罗富马酸二水合物计量吸入器（BGF MDI）是一种吸入性皮质类固醇/长效毒蕈碱拮抗剂/长效β-激动剂固定剂量组合，采用创新的共悬浮输送技术配制，目前正在开发用于治疗慢性阻塞性肺疾病（COPD）。这项随机、I 期、单次剂量、六治疗、四周期、交叉研究（NCT01980615）考察了三种剂量的 BGF MDI（320/14.4/10μg[相当于布地奈德/格隆溴铵/福莫特罗富马酸 320/18/9.6μg]、160/14.4/10μg 和 80/14.4/10μg）、两种剂量的布地奈德/福莫特罗富马酸二水合物固定剂量组合（BUD/FORM MDI 320/9μg 和 160/9μg；未使用共悬浮输送技术）和一种格隆溴铵/福莫特罗富马酸二水合物共悬浮输送技术 MDI（GFF MDI 14.4/10μg）在健康志愿者（18-45 岁）中的药代动力学（PK）和安全性特征。PK 参数包括从 0 到 12 小时的血浆浓度-时间曲线下面积（AUC）、直至最后可测量浓度的 AUC（AUC）、最大血浆浓度（C）和最大血浆浓度时间（t）。整个研究期间监测安全性。在 84 名随机分组的受试者中，有 76 名完成了研究。BGF MDI 320/14.4/10μg 在布地奈德的 C、AUC 和 AUC 方面与 BUD/FORM MDI 320/9μg 具有生物等效性（主要目标）。布地奈德成分在 BGF MDI 80/14.4/10μg 和 BGF MDI 160/14.4/10μg 之间以及 BGF MDI 160/14.4/10μg 和 BGF MDI 320/14.4/10μg 之间观察到剂量比例性。在 BGF MDI 320/14.4/10μg 治疗后，与 GFF MDI 14.4/10μg 相比，糖波铵和福莫特罗的全身暴露相似。各治疗组的不良事件发生率为 3.7-17.9%，无严重不良事件。总之，BGF MDI 320/14.4/10μg 与 BUD/FORM MDI 320/9μg 具有相似的布地奈德 PK 特征。当布地奈德与格隆溴铵和福莫特罗富马酸二水合物联合使用时，未观察到 PK 药物相互作用。这些数据支持在 COPD 中未来的 BGF MDI 临床试验中使用布地奈德 320μg 和 160μg。
