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Tytuł:
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Pharmacokinetics of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler formulated using co-suspension delivery technology after single and chronic dosing in patients with COPD.
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Autorzy:
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Dunn LJ; Clinical Research of West Florida, Clearwater, FL, USA. Electronic address: .
Kerwin EM; Clinical Research Institute of Southern Oregon, Medford, OR, USA. Electronic address: .
DeAngelis K; Formerly of AstraZeneca, Durham, NC, USA. Electronic address: .
Darken P; AstraZeneca, Morristown, NJ, USA. Electronic address: .
Gillen M; AstraZeneca, Gaithersburg, MD, USA. Electronic address: .
Dorinsky P; AstraZeneca, Durham, NC, USA. Electronic address: .
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Źródło:
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Pulmonary pharmacology & therapeutics [Pulm Pharmacol Ther] 2020 Feb; Vol. 60, pp. 101873. Date of Electronic Publication: 2019 Dec 10.
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Typ publikacji:
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Clinical Trial, Phase I; Clinical Trial, Phase III; Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: London : Academic Press
Original Publication: London ; New York : Academic Press, c1997-
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MeSH Terms:
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Bronchodilator Agents/*administration & dosage
Budesonide/*pharmacokinetics
Drug Delivery Systems/*methods
Formoterol Fumarate/*pharmacokinetics
Glycopyrrolate/*pharmacokinetics
Pulmonary Disease, Chronic Obstructive/*drug therapy
Administration, Inhalation ; Adult ; Aged ; Aged, 80 and over ; Bronchodilator Agents/blood ; Bronchodilator Agents/pharmacokinetics ; Budesonide/administration & dosage ; Budesonide/blood ; Double-Blind Method ; Drug Combinations ; Female ; Formoterol Fumarate/administration & dosage ; Formoterol Fumarate/blood ; Glycopyrrolate/administration & dosage ; Glycopyrrolate/blood ; Humans ; Male ; Metered Dose Inhalers ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/metabolism ; Random Allocation
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Contributed Indexing:
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Keywords: Budesonide; Chronic obstructive pulmonary disease; Co-suspension delivery technology; Formoterol fumarate; Glycopyrrolate; Pharmacokinetics
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Molecular Sequence:
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ClinicalTrials.gov NCT03250182; NCT02497001
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Substance Nomenclature:
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0 (Bronchodilator Agents)
0 (Drug Combinations)
51333-22-3 (Budesonide)
V92SO9WP2I (Glycopyrrolate)
W34SHF8J2K (Formoterol Fumarate)
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Entry Date(s):
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Date Created: 20191217 Date Completed: 20210212 Latest Revision: 20210212
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Update Code:
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20240105
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DOI:
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10.1016/j.pupt.2019.101873
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PMID:
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31841699
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Background: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, is a triple fixed-dose combination in late-stage clinical development for chronic obstructive pulmonary disease (COPD).
Methods: We conducted two studies to characterize the pharmacokinetic (PK) profile of BGF MDI in patients with COPD: (i) a phase I, open-label, single and chronic (7-day) dosing study (NCT03250182) with one treatment arm (BGF MDI 320/18/9.6 μg); and (ii) a PK sub-study of KRONOS (NCT02497001), a phase III, randomized, double-blind study in which patients received 24 weeks' treatment with BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 320/9 μg. PK parameters in both studies included maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from 0 to 12h (AUC 0-12 ).
Results: In the phase I PK study (30 patients), budesonide and glycopyrronium C max were comparable after single and chronic dosing of BGF MDI (accumulation ratio [R AC ] 95% and 107%, respectively) whereas C max for formoterol was slightly higher after chronic dosing (R AC 116%). AUC 0-12 for budesonide, glycopyrronium, and formoterol were higher following chronic versus single dosing, with an R AC of 126%, 179%, and 143%, respectively. After 7 days' dosing, AUC 0-12 and C max for all three components of BGF MDI were similar to those in the KRONOS PK sub-study (202 patients) at Week 24. In the latter sub-study, C max and AUC 0-12 at Week 24 were generally comparable across treatments for budesonide (geometric mean ratios [GMR] of 96%-109% for BGF MDI vs BFF MDI or BUD/FORM DPI), glycopyrronium (GMR of 88%-100% for BGF MDI vs GFF MDI), and formoterol (GMR of 80%-113% for BGF MDI vs GFF MDI or BFF MDI).
Conclusions: Steady-state PK parameters of budesonide, glycopyrronium, and formoterol were similar after 7 days' dosing in the phase I PK study and after 24 weeks in the KRONOS PK sub-study. Systemic exposure to budesonide, glycopyrronium, and formoterol was generally comparable across treatments in the KRONOS PK sub-study, suggesting no meaningful drug-drug or within-formulation PK interactions.
(Copyright © 2019 AstraZeneca. Published by Elsevier Ltd.. All rights reserved.)
