Comparison of Formoterol, Glycopyrrolate, and Beclomethasone Dipropionate Pharmacokinetic Profile after Inhaled Administration as pMDI Using HFA134a or HFA152a Propellant: Preclinical Assessment of Drug Exposure in Sprague-Dawley Rat Model.
Alessandro Fioni, Giandomenico Brogin, Paola Puccini, Andrew Dennis Allen, Daniela Miglietta, Erika Cuoghi, Enrico Zambelli, Loredana Battipaglia
{"title":"Comparison of Formoterol, Glycopyrrolate, and Beclomethasone Dipropionate Pharmacokinetic Profile after Inhaled Administration as pMDI Using HFA134a or HFA152a Propellant: Preclinical Assessment of Drug Exposure in Sprague-Dawley Rat Model.","authors":"Alessandro Fioni, Giandomenico Brogin, Paola Puccini, Andrew Dennis Allen, Daniela Miglietta, Erika Cuoghi, Enrico Zambelli, Loredana Battipaglia","doi":"10.1089/jamp.2024.0019","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Background:</i></b> A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate is approved in some geographic areas as pressurized metered dose inhaler (pMDI) formulation for the treatment of asthma and chronic obstructive pulmonary disease. Current pMDIs use hydrofluoroalkanes (HFAs) as a propellant, such as 1,1,1,2-tetrafluoroethane (HFA134a), that have a high global warming potential (GWP), but their use is being progressively lowered to reduce impact on climate. One option to reduce the carbon footprint of the pMDI products while preserving pMDIs as a therapeutic option is reformulating the current pMDIs using low GWP propellants, such as 1,1-difluoroethane (HFA152a). Nevertheless, pharmaceutical, clinical, and regulatory challenges need to be considered when reformulating a pMDI. A nonclinical study in rodents has been performed to support the formulation work and optimize the design of the bioequivalence study in humans. <b><i>Methods:</i></b> A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate (BDP) as pMDI with the two propellants HFA134a or HFA152a was administered by inhalation to Sprague-Dawley rats, using inhalation tower, to assess the impact of the propellant on the PK profile of the active components. After administration, serial blood samples were taken from each rat, and plasma aliquots were analyzed by HPLC-MS/MS. <b><i>Results:</i></b> Inhalation administration to rats of the fixed triple combination as pMDI showed similar PK profile for formoterol, glycopyrrolate, and BDP with the two propellants. Exposure parameters C<sub>max</sub> and AUC<sub>last</sub> of the three active ingredients were compared, showing no statistically significant differences in the systemic exposure between the two treatment groups. Higher interanimal variability was observed for the metabolite beclomethasone 17-monopropionate, likely due to individual differences in the metabolite generation. <b><i>Conclusions:</i></b> Considering these data, it was possible to conclude that replacing propellant HFA134a with HFA152a in a newly developed formulation had no significant impact on the plasmatic PK profile of formoterol, glycopyrrolate, and BDP in rats after inhalation administration using inhalation towers.</p>","PeriodicalId":14940,"journal":{"name":"Journal of Aerosol Medicine and Pulmonary Drug Delivery","volume":" ","pages":""},"PeriodicalIF":2.0000,"publicationDate":"2024-09-26","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.2024.0019","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
Background: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate is approved in some geographic areas as pressurized metered dose inhaler (pMDI) formulation for the treatment of asthma and chronic obstructive pulmonary disease. Current pMDIs use hydrofluoroalkanes (HFAs) as a propellant, such as 1,1,1,2-tetrafluoroethane (HFA134a), that have a high global warming potential (GWP), but their use is being progressively lowered to reduce impact on climate. One option to reduce the carbon footprint of the pMDI products while preserving pMDIs as a therapeutic option is reformulating the current pMDIs using low GWP propellants, such as 1,1-difluoroethane (HFA152a). Nevertheless, pharmaceutical, clinical, and regulatory challenges need to be considered when reformulating a pMDI. A nonclinical study in rodents has been performed to support the formulation work and optimize the design of the bioequivalence study in humans. Methods: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate (BDP) as pMDI with the two propellants HFA134a or HFA152a was administered by inhalation to Sprague-Dawley rats, using inhalation tower, to assess the impact of the propellant on the PK profile of the active components. After administration, serial blood samples were taken from each rat, and plasma aliquots were analyzed by HPLC-MS/MS. Results: Inhalation administration to rats of the fixed triple combination as pMDI showed similar PK profile for formoterol, glycopyrrolate, and BDP with the two propellants. Exposure parameters Cmax and AUClast of the three active ingredients were compared, showing no statistically significant differences in the systemic exposure between the two treatment groups. Higher interanimal variability was observed for the metabolite beclomethasone 17-monopropionate, likely due to individual differences in the metabolite generation. Conclusions: Considering these data, it was possible to conclude that replacing propellant HFA134a with HFA152a in a newly developed formulation had no significant impact on the plasmatic PK profile of formoterol, glycopyrrolate, and BDP in rats after inhalation administration using inhalation towers.
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.