评估使用低全球升温潜能值推进剂通过加压计量吸入器给药的二丙酸倍氯米松/福莫特罗烟酸酯/溴化甘草酸铵的药代动力学。

IF 3.3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
François Rony , Mauro Cortellini , Alessandro Guasconi , Kusum S. Mathews , Annalisa Piccinno , Gianluigi Poli , Frédéric Vanhoutte , Jelle Klein
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引用次数: 0

摘要

导言:加压计量吸入器(pMDIs)正在逐步减少使用全球升温潜能值高的推进剂(如 HFA-134a)。改用干粉吸入器在临床上不一定对所有患者都可行;一种替代方法是使用全球变暖潜能值低的推进剂重新配制。目前正在使用全球升温潜能值较低的推进剂 HFA-152a 重新配制。本手稿报告了三项研究,比较了使用 HFA-152a 和 HFA-134a 通过 pMDI 给药的 BDP/FF/GB 药代动力学。在研究 1 和研究 2 中,受试者吸入四口 BDP/FF/GB(研究 1:100/6/12.5 μg [中等强度 BDP];研究 2:200/6/12.5 μg [高强度]),在其中两个时段摄入活性炭(每种推进剂一次)。所有三项研究都比较了 HFA-152a 与 HFA-134a 在肺部的可用性以及倍氯米松-17-单丙酸酯(B17MP;BDP 的活性代谢物)、BDP、福莫特罗和 GB 的全身暴露量。结果在研究 1 和研究 2 中,除研究 2 中的 GB Cmax(90 % CI 上限为 125.11 %)外,全身暴露生物等效性(即无木炭阻滞的比较)均得到证实。对于肺部可用性(即使用木炭块进行比较),B17MP 和福莫特罗在两项研究中均表现出生物等效性,BDP 在研究 2 中也表现出生物等效性;在研究 1 中,BDP 的 Cmax 上限 CI 为 126.96 %,AUC0-t 上限 CI 为 127.34 %)。在研究 1 中,GB AUC0-t 的下限 CI 为 74.54%;在研究 2 中,Cmax 和 AUC0-t 的上限分别为 135.64% 和 129.12%。在研究 3 中,BDP、B17MP 和 BDP/FF/GB 两种强度的福莫特罗均符合生物等效性标准,GB AUC0-t 符合标准,但 Cmax 不符合标准。结论总体而言,虽然不能对所有分析物得出正式的生物等效性结论,但这些数据表明新制剂与现有的 BDP/FF/GB pMDI 制剂具有治疗等效性,因此支持使用全球变暖潜能值低的推进剂重新制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant

Introduction

Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential.

The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a.

Methods

The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer.

All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration–time curve between time zero and the last quantifiable timepoint (AUC0–t) for the analytes were between 80 and 125 %.

Results

In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0–t). In Study 1, GB AUC0–t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0–t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0–t, although not for Cmax. Both formulations were similarly well tolerated in all three studies.

Conclusions

Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.

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来源期刊
CiteScore
6.20
自引率
0.00%
发文量
41
审稿时长
42 days
期刊介绍: Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews. Research Areas Include: • All major diseases of the lung • Physiology • Pathology • Drug delivery • Metabolism • Pulmonary Toxicology.
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