背景:气候危机对人类健康和福祉构成直接威胁,要求跨部门紧急适应,包括医疗保健。使用具有较低全球变暖潜势(GWP)的新型推进剂开发对气候紧急情况更敏感的加压计量吸入器(MDI),但药代动力学(PK)参数与目前销售的MDI相当,是减少医疗保健对呼吸系统疾病对气候变化影响的重要一步。这项研究评估了三种不同推进剂配方之间每次致动的布地奈德/格隆溴铵/富马酸福莫特罗(BGF)160/9/4.8μg的固定剂量组合的各个成分的相对生物利用度。
方法:健康男性参与者(年龄18-60岁)随机分为单盲,三个时期,单剂量,单中心,交叉研究(NCT04600505)。将用两种具有低GWP的新型推进剂(氢氟烯烃-1234ze[HFO];氢氟碳化合物-152a[HFC])配制的BGFMDI的PK和安全性和耐受性曲线与用目前市售参考产品(氢氟烷烃-134a[HFA])中使用的推进剂配制的BGFMDI进行了比较。这项研究包括一个筛选期,三个治疗期(每个剂量之间有3至7天的清除期),和后续行动。评估的主要PK参数是观察到的最大血浆浓度(Cmax),血浆浓度曲线下面积(AUC)从时间零外推至无穷大(AUCinf),和从时间零到最后可定量分析物浓度(AUClast)的时间的AUC。该研究没有统计学证明生物等效性。
结果:47名参与者完成了研究,24名参与者可进行PK评估。全身暴露,基于几何平均比率(90%置信区间),从标准MDI中交付的测试推进剂中的每个BGF组分与AUClast的参考推进剂相当(HFO与HFA:布地奈德,107.30[94.53,121.90];格隆溴铵,106.10[86.18,130.60];福莫特罗,98.13[86.44,111.40];HFC与HFA:布地奈德,98.80[84.59,115.40];格隆溴铵,99.71[80.84,123.00];福莫特罗,107.00[88.82,128.90]);AUCinf(在可评估的情况下)和Cmax遵循相同的趋势。没有严重不良事件或导致治疗中断的不良事件。没有观察到新的安全信号。
结论:与HFA参考推进剂相比,两种测试推进剂(HFO和HFC)的全身BGF成分暴露相似,在研究人群中具有可接受的安全性。因此,两种新型低全球升温潜能值推进剂都显示出强大的潜力,作为开发对气候危机更敏感的计量吸入器的候选者,这是改善医疗保健对环境有害影响的重要一步。需要在更大的研究中进行进一步的调查。
BACKGROUND: The climate crisis poses an immediate threat to human health and well-being, demanding urgent adaptions across sectors, including healthcare. The development of pressurized metered dose inhalers (MDIs) with greater sensitivity to the climate emergency using novel propellants with lower global warming potentials (GWPs), but comparable pharmacokinetic (PK) parameters to currently marketed MDIs, is a vital step toward reducing the impact of healthcare for respiratory disorders on climate change. This study evaluated the relative bioavailabilities of the individual components of a fixed-dose combination of budesonide/glycopyrrolate/formoterol fumarate (BGF) 160/9/4.8 μg per actuation between three different propellant formulations.
METHODS: Healthy male participants (aged 18-60 years) were randomized into a single-blind, three-period, single-dose, single-center, crossover study (NCT04600505). The PK and safety and tolerability profiles of BGF MDI formulated with two novel propellants with low GWP (hydrofluoroolefin-1234ze [HFO]; hydrofluorocarbon-152a [HFC]) were compared with BGF MDI formulated with the propellant used in the currently marketed reference product (hydrofluoroalkane-134a [HFA]). The study included a screening period, three treatment periods (with 3- to 7-day washout periods between each dose), and a follow-up. The primary PK parameters assessed were maximum observed plasma concentration (Cmax), area under the plasma concentration curve (AUC) from time zero extrapolated to infinity (AUCinf), and AUC from time zero to the time of the last quantifiable analyte concentration (AUClast). The study was not powered to statistically demonstrate bioequivalence.
RESULTS: Forty-seven participants completed the study, and 24 participants were evaluable for PK assessments. Systemic exposure, based on geometric mean ratios (90% confidence interval), to each BGF component from the test propellants delivered in a standard MDI was comparable with the reference propellant for AUClast (HFO vs. HFA: budesonide, 107.30 [94.53, 121.90]; glycopyrrolate, 106.10 [86.18, 130.60]; formoterol, 98.13 [86.44, 111.40]; HFC vs. HFA: budesonide, 98.80 [84.59, 115.40]; glycopyrrolate, 99.71 [80.84, 123.00]; formoterol, 107.00 [88.82, 128.90]); AUCinf (where evaluable) and Cmax followed the same trend. There were no serious adverse events or adverse events leading to treatment discontinuation. No new safety signals were observed.
CONCLUSIONS: Systemic BGF component exposure was similar for both test propellants (HFO and HFC) compared with the HFA reference propellant, with an acceptable safety profile in the studied population. Therefore, both novel low GWP propellants show strong potential as candidates for development of MDIs with greater sensitivity to the climate crisis, a vital step toward ameliorating the detrimental impact of healthcare on the environment. Further investigation in larger studies is warranted.