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 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.

Pharmacokinetics, pharmacodynamics and safety of a novel extrafine BDP/FF/GB combination delivered via metered-dose inhaler in healthy Chinese subjects.

BACKGROUND: BDP/FF/GB pMDI is a novel triple fixed-dose combination of extra-fine inhalation aerosol beclomethasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB). Limited data on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of BDP/FF/GB fixed-dose combination in healthy subjects was available. PURPOSES: This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of BDP/FF/GB pMDI in healthy Chinese subjects. METHODS: This is an open-label, parallel-group, randomized, single and multiple dose study. In the single dose group, subjects received single supra-therapeutic inhaled dose of BDP/FF/GB pMDI (BDP/FF/GB 400/24/50 µg). In the multiple dose group, subjects received therapeutic inhaled dose of BDP/FF/GB pMDI (BDP/FF/GB 200/12/25 µg), twice daily, for 7 consecutive days. Plasma BDP, B17MP, formoterol and GB were determined by a validated ultra performance liquid chromatography method with tandem mass spectrometric detection (UPLC/MS-MS). Heart rate (HR), QTcF, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated as the surrogate indicators of pharmacodynamic effects. RESULTS: A total of 24 subjects were randomized and 22 (11 in each group) completed the study. The dose adjusted pharmacokinetic profiles of BDP, beclomethasone-17-monopropionate (B17MP, the most active metabolite of BDP), formoterol and GB were overall similar in therapeutic and supra- therapeutic dose group, showing dose proportional increase of the systemic exposure to BDP, B17MP, formoterol and GB. The pharmacodynamic variables were within the normal range and showed no significant difference between the two groups. All the treatment-emergent adverse events (TEAEs) were mild and no severe TEAE was reported. CONCLUSIONS: Dose adjusted PK profiles were similar between therapeutic and supra-therapeutic dose for all compounds, nearly dose proportional systemic exposure to B17MP, formoterol and GB after BDP/FF/GB pMDI administration in healthy Chinese subjects. BDP/FF/GB pMDI was safe and well tolerated in healthy Chinese subjects. The PK profiles were comparable to previously published data from Western European healthy Caucasian subjects.

Beta2 -adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses.

While studies have demonstrated substantial differences in beta2 -adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta2 -adrenergic ligand racemic (rac)-formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta2 -adrenergic agonist in skeletal muscle is absent despite its promising data on muscle anabolism in humans. Using a sensitive ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay, we determined disposition of (R,R)-formoterol and (S,S)-formoterol in plasma and skeletal muscle samples from 11 non-asthmatic men who had inhaled rac-formoterol at therapeutic doses (2 × 27 µg). Mean (SD) concentrations of (R,R)- and (S,S)-formoterol in plasma and in muscle biopsies of the vastus lateralis 1 hour after inhalation of formoterol were 31 (15) and 45 (18) pg × mL-1 for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg × mgwet wt -1 , respectively, in muscle. Formoterol exhibited different enantioselective disposition in plasma and muscle (p < 0.0001). In plasma, mean log (R,R):(S,S)-formoterol ratio was lower than 0 [-0.17(0.07), p < 0.0001], whereas in muscle, mean log (R,R):(S,S)-formoterol ratio was slightly higher than 0 [0.04(0.07), p < 0.05]. Log (R,R):(S,S)-formoterol ratio in muscle was related to muscle fiber-type composition. Furthermore, formoterol induced an approximately two-fold increase in muscle p-PKASer/thr phosphorylation (p < 0.01), indicating a substantial beta2 -adrenergic response. Collectively, these findings suggest that formoterol exhibits modest enantioselective disposition in plasma after inhaled therapy in humans, which appear related to a greater (R,R)-enantiomer disposition in skeletal muscle that may be dependent on fiber-type composition.

Effect of a spacer on total systemic and lung bioavailability in healthy volunteers and in vitro performance of the Symbicort® (budesonide/formoterol) pressurized metered dose inhaler.

INTRODUCTION: Many patients with chronic obstructive pulmonary disease or asthma experience difficulties in coordinating inhalation with pressurized metered-dose inhaler (pMDI) actuation. The use of a spacer device can improve drug delivery in these patients. The aim of this study was to establish the relative bioavailability of single doses of Symbicort® (budesonide/formoterol) pMDI 160/4.5 µg/actuation (2 actuations) used with and without a spacer device. In addition, an in vitro study was conducted to characterize performance of the inhaler when used in conjunction with a spacer device. METHODS: A Phase I, randomized, open-label, single-dose, single-center, crossover study in 50 healthy volunteers (NCT02934607) assessed the relative bioavailability of single-dose Symbicort® pMDI 160/4.5 µg/actuation (2 actuations) with and without a spacer (AeroChamber Plus® Flow-Vu®). Inhaled doses were administered without or with activated charcoal (taken orally) to estimate total systemic exposure and exposure through the lung, respectively. The in vitro study characterized the effect of the spacer with respect to delivered dose, fine particle dose, and dose during simulated breathing of budesonide and formoterol. RESULTS: In terms of total systemic exposure, use of the spacer increased the relative bioavailability determined by AUC(0-last) and Cmax by 68% (spacer:no spacer treatment ratio, 167.9%; 90% CI, 144.1 to 195.6) and 99% (ratio, 198.7%; 90% CI, 164.4 to 240.2) for budesonide, and 77% (ratio, 176.6%; 90% CI, 145.1 to 215.0) and 124% (ratio, 223.6%; 90% CI, 189.9 to 263.3) for formoterol, respectively, compared with pMDI alone. Similarly, the lung exposure of budesonide and formoterol increased (AUC(0-last) and Cmax by 146% [ratio, 246.0%; 90% CI, 200.7 to 301.6] and 127% [ratio, 226.5%; 90% CI, 186.4 to 275.4] for budesonide, and 173% [ratio, 272.8%; 90% CI, 202.5 to 367.4] and 136% [ratio, 236.2%; 90% CI, 192.6 to 289.6] for formoterol, respectively) when the pMDI was administered through the spacer. When assessed by AUC(0-last) quartile without spacer, subjects in the lowest exposure quartile (indicating poor inhalation technique) with Symbicort® pMDI 160/4.5 µg/actuation (2 actuations) had markedly increased total systemic and lung exposure when the same dose was administered with the spacer. In contrast, for subjects in the highest exposure quartile with pMDI alone, total systemic and lung exposure of formoterol and budesonide was similar with and without the spacer. In the in vitro study, the fine particle dose (<5 µm) of both budesonide and formoterol from the spacer at delay time (i.e. pause period after actuation) = 0 s (instantaneous) after actuation was similar to the fine particle dose when not using the spacer. The delivered doses of budesonide and formoterol from the spacer were both lower compared with the doses administered without the spacer. There was also a decrease in delivered dose with increasing delay time. CONCLUSIONS: The clinical study demonstrated that in subjects with poor inhalation technique the use of the AeroChamber Plus® Flow-Vu® spacer increased the bioavailability of Symbicort® pMDI to a level observed in subjects with good inhalation technique without a spacer. The findings from the in vitro study support the fine particle dose characteristics of Symbicort® pMDI with the AeroChamber Plus® Flow-Vu® spacer.

Randomized study of the effects of Aerochamber Plus® Flow-Vu® on the efficacy, pharmacokinetics and safety of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler in patients with chronic obstructive pulmonary disease.

OBJECTIVES: This study compared the efficacy, pharmacokinetics (PK), and safety of GFF MDI (Bevespi Aerosphere®), a fixed-dose combination of glycopyrronium and formoterol fumarate dihydrate (14.4/10 µg) delivered by a metered dose inhaler (MDI) formulated using innovative co-suspension delivery technology, in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) with and without the Aerochamber Plus® Flow-Vu® valved holding chamber (VHC). METHODS: In this multicenter, open-label, crossover, Phase III study (NCT02454959), patients were randomized to receive GFF MDI 14.4/10 µg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 µg) twice daily for 7 days with and without the VHC. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 8. Steady state PK parameters for glycopyrronium and formoterol (AUC0-12, peak concentration [Cmax] and time to peak concentration [tmax]) were estimated from 12-h plasma concentration time data on Day 8. Safety and tolerability were also assessed throughout. RESULTS: Eighty patients were randomized. On Day 8, the ratio (90% confidence interval [CI]) of least squares mean (LSM) FEV1 AUC0-12 for GFF MDI with VHC (LSM = 1538 mL; n = 67) versus without VHC (LSM = 1516 mL; n = 68) was 101.4% (100.1, 102.7). PK parameters were comparable overall with a slightly higher exposure to glycopyrronium with the VHC. The AUC0-12 geometric LSM ratio (90% CI) for GFF MDI with versus without VHC was 115.99% (99.74, 134.89) for glycopyrronium and 96.66% (86.69, 107.78) for formoterol. GFF MDI with and without VHC were well tolerated with a similar adverse event profile. CONCLUSIONS: The magnitude of bronchodilatory effect was similar with and without a VHC following GFF MDI treatment. This, together with the PK and safety profiles, supports the use of the VHC with GFF MDI for the maintenance treatment of COPD, which could be particularly useful for patients who have difficulty with the coordination of an MDI.

Pharmacokinetics of glycopyrronium/formoterol fumarate dihydrate delivered via metered dose inhaler using co-suspension delivery technology in patients with moderate-to-very severe COPD.

Purpose: The efficacy and tolerability of GFF MDI (Bevespi Aerosphere®), a fixed-dose combination of glycopyrronium (GP)/formoterol fumarate dihydrate (FF) 14.4/10 µg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 µg) delivered by metered dose inhaler (MDI) using innovative co-suspension delivery technology, has been investigated in a Phase III clinical trial program (NCT01854645, NCT01854658, NCT01970878) in patients with COPD. Here, we present findings from a pharmacokinetic (PK) sub-study of NCT01854645 (PINNACLE-1). Methods: PINNACLE-1 was a multicenter, randomized, double-blind, parallel-group, 24 wk chronic-dosing, placebo- and active-controlled study. The PK sub-study assessed the systemic accumulation of glycopyrronium and formoterol following administration of GFF MDI 14.4/10 µg, GP MDI 14.4 µg, or FF MDI 10 µg (all BID) for 12 wks. Plasma for PK analysis was collected for up to 12 h after dosing, on Day 1 and Week 12. Results: Of 2,103 patients randomized in PINNACLE-1, 292 participated in the PK sub-study. The plasma concentration-time profiles of glycopyrronium were similar following treatment with GFF MDI or GP MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 2.30-fold for glycopyrronium. The plasma concentration-time profiles of formoterol were similar following treatment with GFF MDI or FF MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 1.62-fold for formoterol. Conclusion: Overall, the results have characterized the accumulation of glycopyrronium and formoterol associated with GFF MDI, GP MDI, and FF MDI, and indicated that there were no meaningful PK interactions, whether drug-drug or due to formulation, between glycopyrronium and formoterol following treatment with GFF MDI formulated using co-suspension delivery technology.