Pharmacokinetic and Pharmacodynamic Comparison of Fluticasone Propionate/Formoterol Fumarate Administered via a Pressurized Metered-Dose Inhaler and a Novel Breath-Actuated Inhaler in Healthy Volunteers.

IF 2 4区 医学 Q3 RESPIRATORY SYSTEM
Sanjeeva Dissanayake, Gill Mundin, Jo Woodward, Mark Lomax, Prashant Dalvi
{"title":"Pharmacokinetic and Pharmacodynamic Comparison of Fluticasone Propionate/Formoterol Fumarate Administered via a Pressurized Metered-Dose Inhaler and a Novel Breath-Actuated Inhaler in Healthy Volunteers.","authors":"Sanjeeva Dissanayake,&nbsp;Gill Mundin,&nbsp;Jo Woodward,&nbsp;Mark Lomax,&nbsp;Prashant Dalvi","doi":"10.1089/jamp.2022.0064","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Introduction:</i></b> Fluticasone propionate/formoterol fumarate (fluticasone/formoterol) exposures, following administration of Flutiform<sup>®</sup> K-haler<sup>®</sup>, a breath-actuated inhaler (BAI), were compared with the Flutiform pressurized metered-dose inhaler (pMDI) with/without spacer in two healthy volunteer studies. In addition, formoterol-induced systemic pharmacodynamic (PD) effects were examined in the second study. <b><i>Methods:</i></b> Study 1: single-dose, three-period, crossover pharmacokinetic (PK) study with oral charcoal administration. Fluticasone/formoterol 250/10 μg was administered via BAI, pMDI, or pMDI with spacer (pMDI+S). Pulmonary exposure for BAI was deemed no less than for pMDI (primary comparator) if the lower limit of 94.12% confidence intervals (CIs) for BAI:pMDI maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCt) ratios was ≥80%. Study 2: two-stage adaptive design, both stages being single-dose, crossover without charcoal administration. The PK stage compared fluticasone/formoterol 250/10 μg via BAI, pMDI, or pMDI+S. The primary comparisons were as follows: BAI versus pMDI+S for fluticasone and BAI versus pMDI for formoterol. Systemic safety with BAI was deemed no worse than primary comparator if the upper limit of 94.12% CIs for Cmax and AUCt ratios was ≤125%. PD assessment was to be conducted if BAI safety was not confirmed in the PK stage. Based on PK results, only formoterol PD effects were evaluated. The PD stage compared fluticasone/formoterol 1500/60 μg via BAI, pMDI, or pMDI+S; fluticasone/formoterol 500/20 μg pMDI; and formoterol 60 μg pMDI. The primary endpoint was maximum reduction in serum potassium within 4 hours postdose. Equivalence was defined as 95% CIs for BAI versus pMDI+S and pMDI ratios within 0.5-2.0. <b><i>Results:</i></b> Study 1: lower limit of 94.12% CIs for BAI:pMDI ratios >80%. Study 2, PK stage: upper limit of 94.12% CIs for fluticasone (BAI:pMDI+S) ratios <125%; upper limit of 94.12% CIs for formoterol (BAI:pMDI) ratios >125% (for Cmax, not AUCt). Study 2, PD stage: 95% CIs for serum potassium ratios 0.7-1.3 (BAI:pMDI+S) and 0.4-1.5 (BAI:pMDI). <b><i>Conclusions:</i></b> Fluticasone/formoterol BAI performance was within the range observed for the pMDI with/without a spacer. Sponsor: Mundipharma Research Ltd. EudraCT 2012-003728-19 (Study 1) and 2013-000045-39 (Study 2).</p>","PeriodicalId":14940,"journal":{"name":"Journal of Aerosol Medicine and Pulmonary Drug Delivery","volume":"36 2","pages":"65-75"},"PeriodicalIF":2.0000,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Aerosol Medicine and Pulmonary Drug Delivery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/jamp.2022.0064","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: Fluticasone propionate/formoterol fumarate (fluticasone/formoterol) exposures, following administration of Flutiform® K-haler®, a breath-actuated inhaler (BAI), were compared with the Flutiform pressurized metered-dose inhaler (pMDI) with/without spacer in two healthy volunteer studies. In addition, formoterol-induced systemic pharmacodynamic (PD) effects were examined in the second study. Methods: Study 1: single-dose, three-period, crossover pharmacokinetic (PK) study with oral charcoal administration. Fluticasone/formoterol 250/10 μg was administered via BAI, pMDI, or pMDI with spacer (pMDI+S). Pulmonary exposure for BAI was deemed no less than for pMDI (primary comparator) if the lower limit of 94.12% confidence intervals (CIs) for BAI:pMDI maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCt) ratios was ≥80%. Study 2: two-stage adaptive design, both stages being single-dose, crossover without charcoal administration. The PK stage compared fluticasone/formoterol 250/10 μg via BAI, pMDI, or pMDI+S. The primary comparisons were as follows: BAI versus pMDI+S for fluticasone and BAI versus pMDI for formoterol. Systemic safety with BAI was deemed no worse than primary comparator if the upper limit of 94.12% CIs for Cmax and AUCt ratios was ≤125%. PD assessment was to be conducted if BAI safety was not confirmed in the PK stage. Based on PK results, only formoterol PD effects were evaluated. The PD stage compared fluticasone/formoterol 1500/60 μg via BAI, pMDI, or pMDI+S; fluticasone/formoterol 500/20 μg pMDI; and formoterol 60 μg pMDI. The primary endpoint was maximum reduction in serum potassium within 4 hours postdose. Equivalence was defined as 95% CIs for BAI versus pMDI+S and pMDI ratios within 0.5-2.0. Results: Study 1: lower limit of 94.12% CIs for BAI:pMDI ratios >80%. Study 2, PK stage: upper limit of 94.12% CIs for fluticasone (BAI:pMDI+S) ratios <125%; upper limit of 94.12% CIs for formoterol (BAI:pMDI) ratios >125% (for Cmax, not AUCt). Study 2, PD stage: 95% CIs for serum potassium ratios 0.7-1.3 (BAI:pMDI+S) and 0.4-1.5 (BAI:pMDI). Conclusions: Fluticasone/formoterol BAI performance was within the range observed for the pMDI with/without a spacer. Sponsor: Mundipharma Research Ltd. EudraCT 2012-003728-19 (Study 1) and 2013-000045-39 (Study 2).

健康志愿者加压计量吸入器和新型呼吸驱动吸入器给药丙酸氟替卡松/富马酸福莫特罗的药代动力学和药效学比较
在两项健康志愿者研究中,比较了在使用呼吸驱动吸入器(BAI) Flutiform®K-haler®后,丙酸氟替卡松/富马酸福莫特罗(氟替卡松/福莫特罗)暴露与带/不带间隔剂的Flutiform加压计量吸入器(pMDI)。此外,在第二项研究中还检测了福莫特罗诱导的全身药效学(PD)效应。方法:研究1:单剂量、三期、交叉药代动力学(PK)与口服炭给药。氟替卡松/福莫特罗250/10 μg经BAI、pMDI或pMDI加间隔剂(pMDI+S)给药。如果BAI:pMDI最大血浆浓度(Cmax)和血浆浓度-时间曲线下面积(AUCt)比值的94.12%置信区间(CIs)下限≥80%,则认为BAI的肺部暴露不低于pMDI(主要比较物)。研究2:两阶段自适应设计,两阶段均为单剂量,无木炭给药。通过BAI、pMDI、pMDI+S比较氟替卡松/福莫特罗250/10 μg的PK期。主要比较如下:氟替卡松的BAI与pMDI+S比较,福莫特罗的BAI与pMDI比较。如果Cmax和AUCt比值的94.12% ci的上限≤125%,则认为BAI的系统安全性不差于主要比较者。如果在PK阶段未确认BAI的安全性,则进行PD评估。基于PK结果,仅评价福莫特罗PD效应。PD分期通过BAI、pMDI、pMDI+S比较氟替卡松/福莫特罗1500/60 μg;氟替卡松/福莫特罗500/20 μg pMDI;福莫特罗60 μg pMDI。主要终点是给药后4小时内血清钾的最大降低。等效性定义为BAI与pMDI+S和pMDI比值在0.5-2.0范围内的95% CIs。结果:研究1:BAI:pMDI比值>80%时,ci下限为94.12%。研究2,PK期:氟替卡松(BAI:pMDI+S)比值125% (Cmax,非AUCt)的ci上限为94.12%。研究2,PD分期:血清钾比值0.7-1.3 (BAI:pMDI+S)和0.4-1.5 (BAI:pMDI) 95% CIs。结论:氟替卡松/福莫特罗的BAI性能在有/没有间隔剂的pMDI的观察范围内。主办单位:萌蒂制药研究有限公司EudraCT 2012-003728-19(研究1)和2013-000045-39(研究2)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.70
自引率
2.90%
发文量
34
审稿时长
>12 weeks
期刊介绍: Journal of Aerosol Medicine and Pulmonary Drug Delivery is the only peer-reviewed journal delivering innovative, authoritative coverage of the health effects of inhaled aerosols and delivery of drugs through the pulmonary system. The Journal is a forum for leading experts, addressing novel topics such as aerosolized chemotherapy, aerosolized vaccines, methods to determine toxicities, and delivery of aerosolized drugs in the intubated patient. Journal of Aerosol Medicine and Pulmonary Drug Delivery coverage includes: Pulmonary drug delivery Airway reactivity and asthma treatment Inhalation of particles and gases in the respiratory tract Toxic effects of inhaled agents Aerosols as tools for studying basic physiologic phenomena.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信