Pharmacokinetics of Co-Suspension Delivery Technology Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate (BGF MDI) and Budesonide/Formoterol Fumarate Dihydrate (BFF MDI) Fixed-Dose Combinations Compared With an Active Control: A Phase 1, Randomized, Single-Dose, Crossover Study in Healthy Adults

Abstract

This randomized, phase 1, single-dose, crossover study (NCT02189304) compared the 12-hour pharmacokinetic (PK) and safety profiles of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) 320/14.4/10 μg and budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg (both formulated using innovative co-suspension delivery technology) to an active comparator (budesonide/formoterol fumarate dihydrate dry powder inhaler [BUD/FORM DPI] 320/9-μg delivered dose) in healthy adults. The potential for PK interaction between glycopyrronium and budesonide/formoterol within BGF MDI was assessed. Of 72 subjects randomized, 59 completed treatment. Systemic budesonide exposure (primary objective) based on area under the plasma drug concentration-time curve 0-12 hours (AUC_0-12 ; % coefficient of variation) was 1598.38 (49.7), 1657.09 (50.4), and 1276.75 (70.4) pg·h/mL for BGF MDI, BFF MDI, and BUD/FORM DPI, respectively; and formoterol exposure (AUC_0-12 [% coefficient of variation]) was 39.16 (45.9), 39.53 (40.5), and 23.24 (59.2) pg·h/mL, respectively. BGF MDI and BFF MDI were bioequivalent for budesonide and formoterol. All treatments were well tolerated. While systemic exposure to budesonide and formoterol was higher for BGF MDI and BFF MDI than for BUD/FORM DPI, there were no appreciable differences in the incidence of pharmacologically predictable adverse events. This, coupled with the absence of PK interactions, suggests the BGF MDI safety profile will be comparable to BUD/FORM DPI.

Keywords: COPD; co-suspension delivery technology; fixed-dose combination; metered dose inhaler; pharmacokinetics.

Figure 1

Arithmetic mean (±SE) plasma drug concentration‐time profile of (A) budesonide, (B) formoterol, and (C) glycopyrronium (PK population). BFF, budesonide/formoterol fumarate dihydrate; BGF, budesonide/glycopyrronium/formoterol fumarate dihydrate; BUD/FORM, budesonide/formoterol fumarate dihydrate; DPI, dry powder inhaler; MDI, metered dose inhaler; PK, pharmacokinetic; SE, standard error.

Figure 2

Relative bioequivalence of (A) budesonide and (B) formoterol in BGF MDI and BFF MDI (ratio of geometric least squares means [90%CI] for AUC_0‐12 and C_max; PK population). AUC_0‐12, area under the plasma drug concentration‐time curve from 0‐12 hours; BFF, budesonide/formoterol fumarate dihydrate; BGF, budesonide/glycopyrronium/formoterol fumarate dihydrate; CI, confidence interval; C_max, maximum observed plasma concentration; LSM, least squares mean; MDI, metered dose inhaler; PK, pharmacokinetic.