Pharmacokinetics of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler formulated using co-suspension delivery technology after single and chronic dosing in patients with COPD. (February 2020)

• Record Type: Journal Article
• Authors: Dunn, Leonard J.; Kerwin, Edward M.; DeAngelis, Kiernan; Darken, Patrick; Gillen, Michael; Dorinsky, Paul
• Is Part Of: Pulmonary pharmacology & therapeutics. Volume 60(2020)
• Publication Date: 2020-02
• Subjects: Budesonide -- Chronic obstructive pulmonary disease -- Co-suspension delivery technology -- Formoterol fumarate -- Glycopyrrolate -- Pharmacokinetics; AE adverse event -- AUC area under the plasma concentration–time curve -- AUC0–12 area under the plasma concentration–time curve from 0 to 12 h post-dose -- AUC0–tlast area under the plasma concentration–time curve from time 0 to the time of the last measurable plasma concentration -- AUC0–∞ area under the plasma concentration–time curve from time 0 extrapolated to infinity -- BFF budesonide/formoterol fumarate -- BGF budesonide/glycopyrrolate/formoterol fumarate -- BMI body mass index -- BUD/FORM DPI budesonide/formoterol fumarate dry-powder inhaler -- CI confidence interval -- Cmax maximum observed plasma concentration -- COPD chronic obstructive pulmonary disease -- CV coefficient of variation -- ECG electrocardiogram -- FEV1 forced expiratory volume in 1 s -- GFF glycopyrrolate/formoterol fumarate -- ICS inhaled corticosteroid -- LABA long-acting β2-agonist -- LAMA long-acting muscarinic antagonist -- MDI metered dose inhaler -- N/A not available -- PK pharmacokinetic -- RAC accumulation ratio -- SD standard deviation -- SE standard error -- TEAE treatment-emergent adverse event -- tmax time to maximum observed plasma concentration; Respiratory organs -- Diseases -- Chemotherapy -- Periodicals; 615.7205
• DOI: 10.1016/j.pupt.2019.101873
• Languages: English
• ISSNs: 1094-5539

Abstract

Abstract: 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 (Cmax ) and area under the plasma concentration–time curve from 0 to 12h (AUC0–12 ). Results: In the phase I PK study (30 patients), budesonide and glycopyrronium Cmax were comparable after single and chronic dosing of BGF MDI (accumulation ratio [RAC ] 95% and 107%, respectively) whereas Cmax for formoterol was slightly higher after chronic dosing (RAC 116%). AUC0–12 for budesonide, glycopyrronium, and formoterol were higher following chronic versus single dosing, with an RAC of 126%, 179%, and 143%, respectively. After 7 days' dosing, AUC0–12 and Cmax 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, Cmax and AUC0–12 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.