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

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 mu g); 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 mu g, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 mu g, budesonide/formoterol fumarate (BFF) MDI 320/9.6 mu g, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 320/9 mu g. 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.