Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant.

INTRODUCTION: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. METHODS: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 µg [medium-strength BDP]; Study 2: 200/6/12.5 µg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC0-t) for the analytes were between 80 and 125 %. RESULTS: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0-t). In Study 1, GB AUC0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0-t, although not for Cmax. Both formulations were similarly well tolerated in all three studies. CONCLUSIONS: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.

Pharmacokinetics of extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide in adolescent and adult patients with asthma.

The single-inhaler extrafine formulation triple combination beclometasone dipropionate (BDP), formoterol fumarate (FF) plus glycopyrronium bromide (GB) is available for asthma management in adults. Its use in adolescents has not yet been evaluated. This study investigated the pharmacokinetic profile of BDP/FF/GB in adults and adolescents, with the aim of ruling out higher plasma exposure in adolescents compared to adults. In this open-label, non-randomized study, patients with asthma aged 12-17 (adolescents) and 18-64 years (adults) self-administered a single dose of BDP/FF/GB 400/24/50 µg via pressurized metered-dose inhaler (pMDI). The primary objective was to rule out higher systemic exposure to beclometasone 17-monopropionate (B17MP; active metabolite of BDP), formoterol, and GB in terms of the area under the plasma concentration-time curve from 0 to the last quantifiable concentration (AUC0-t ) in adolescents versus adults. A total of 40 adolescents and 40 adults entered the study (mean age of 14.8 and 43.6 years, respectively). The primary objective (AUC0-t ) was met, with the upper 90% confidence interval of the geometric mean ratio between adolescents and adults <125% for B17MP (point estimate 79.28 [90% CI 71.19; 88.29]), formoterol (88.68 [77.71; 101.20]) and GB (85.49 [72.96; 100.16]). All secondary pharmacokinetic endpoints supported the primary, with pharmacodynamic (safety) and tolerability results similar in the two populations. In conclusion, systemic exposure to extrafine BDP/FF/GB pMDI in adolescents was not higher than that in adults. Furthermore, there were no safety or tolerability signals to warrant a reduction in the dose of BDP/FF/GB for adolescents with asthma.

Population Pharmacokinetic Analysis of Indacaterol/Glycopyrronium/Mometasone Furoate After Administration of Combination Therapies Using the Breezhaler® Device in Patients with Asthma.

BACKGROUND AND OBJECTIVE: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. METHODS: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. RESULTS: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. CONCLUSION: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

BACKGROUND: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d. METHODS: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 µg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 µg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14. RESULTS: In total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed. CONCLUSION: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups. TRIAL REGISTRATION: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.

Variables Affecting Delivery of Glycopyrronium Tosylate Through Human Skin In Vitro.

BACKGROUND: Hyperhidrosis is a condition characterized by excessive sweating beyond what is required for normal thermal regulation. It can involve multiple body areas including the axillae, palms, soles, or craniofacial regions. Glycopyrronium tosylate (GT) is a topical anticholinergic approved by the FDA (2018) for treatment of primary axillary hyperhidrosis in patients 9 years and older. OBJECTIVE: Gain insight into variables (anatomical sites, occlusion, exposure time) affecting GT delivery into human skin. METHODS: Human skin from different anatomical regions (palmar, plantar, axillary, and abdominal skin) was mounted into flow-through diffusion cells (MedFlux-HT®). GT solution (2.4%) was applied at 10 mg/cm2 and the receiving fluid was collected every 2 hours, for 24 hours. GT penetration was determined using LC/MS/MS. The effect of occlusion was assessed by covering the skin with either parafilm or saran wrap, and the effect of exposure time was assessed by incubating the skin for 5, 15, or 60 minutes before washing off the GT from the surface. RESULTS: GT delivery through palmar and plantar skin was up to 40-fold lower compared to delivery through axillary or abdominal skin. Occlusion increased GT delivery up to 10-fold. Reducing exposure time from 24 hours to either 5, 15, or 60 minutes, decreased GT flux by 90%. However, occlusion during these varied exposure times was able to restore GT delivery to levels found in the 24-hour exposed, non-occluded control group. CONCLUSION: These in vitro skin penetration studies showed that skin thickness, exposure time, and occlusion substantially influenced GT delivery, potentially impacting clinical trial design. J Drugs Dermatol. 2020;19(11): doi:10.36849/JDD.2020.5062.

Validation of a sensitive and specific LC-MS/MS method and application to evaluate the systemic exposure and bioavailability of glycopyrrolate via different drug delivery approaches/devices.

A specific and sensitive LC-MS/MS method using d3 -glycopyrrolate as the internal standard (IS) was developed for the quantitative determination of glycopyrrolate (GLY) in human plasma over a concentration range of 4.00-2000 pg/ml. The GLY and IS were extracted using a solid-phase extraction cartridge, then eluted with 0.5% formic acid in 70:30 acetonitrile-water. The eluate was directly injected into an Agilent Pursuit 5PFP column for analysis using an isocratic mobile phase of 50:50 A:B at a flow-rate of 0.500 ml/min (A, 10 mm ammonium acetate in 1% formic acid; B, methanol). The MS detection was in positive mode by monitoring m/z 318.3 → 116.1 (GLY) and 321.3 → 119.1 (IS). The method validation showed the linearity of r2 ≥ 0.9960, intra-/inter-run precisions of ≤11.1% coefficient of variation and accuracies ranging from -2.5 to 12.8% relative error for all levels of quality control samples. This method was successfully employed to support a clinical study to compare absorption and bioavailability of GLY administered by a Magnair® eFlow nebulizer to a Seebri® Breezhaler® with/without a charcoal blockade of gastric absorption. By comparison with intravenous administration, respective bioavailabilities of ~15% for GLY/Magnair and ~22% for the Seebri Breezhaler were found. The bioanalytical reliability was also demonstrated by satisfactory incurred sample reanalysis performance.

Relative Bioavailability of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Administered With and Without a Spacer: Results of a Phase I, Randomized, Crossover Trial in Healthy Adults.

PURPOSE: The triple combination therapy budesonide/glycopyrrolate/formoterol fumarate in a metered dose inhaler (BGF MDI), formulated by using innovative co-suspension delivery technology, is a new inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination for the maintenance treatment of COPD. For some patients, the use of an MDI may be optimized with a spacer. This Phase I study assessed the effect of a spacer on lung exposure, total systemic exposure, and safety of BGF MDI 320/36/9.6 µg in healthy subjects. METHODS: This randomized, open-label, crossover study assessed the pharmacokinetic and safety profiles of BGF MDI in healthy adult subjects who received a single dose of BGF MDI 320/36/9.6 µg (administered as 2 inhalations with 160/18/4.8 µg per actuation) in 4 regimens: without spacer and no charcoal; with spacer and no charcoal; without spacer and with charcoal; and with spacer and with charcoal. Primary objectives were to assess total systemic exposure (without charcoal) and lung exposure (with charcoal) of budesonide, glycopyrronium, and formoterol administered as BGF MDI with and without a spacer. Safety was also assessed. FINDINGS: In total, 56 subjects were randomized (mean age, 29.9 years; 60.7% male, 17.9% former smokers). For systemic exposure (without charcoal), the spacer/without spacer ratio, expressed as a percentage (intrasubject %CV) of Cmax and AUC0-tlast, respectively, was 152.0 (47.5) and 132.8 (43.6) for budesonide, 240.6 (80.2) and 154.7 (73.4) for glycopyrronium, and 165.6 (50.7) and 98.6 (53.8) for formoterol. For lung exposure (with charcoal), the spacer/without spacer ratio percentage (%CV) of Cmax and AUC0-tlast, respectively, was 183.6 (65.9) and 198.4 (71.5) for budesonide, 262.0 (91.8) and 373.9 (120.7) for glycopyrronium, and 222.9 (56.3) and 385.2 (147.0) for formoterol. Subjects who were judged to have suboptimal inhalation technique without a spacer (those in the lowest drug exposure quartile based on AUC0-tlast) had the greatest increase in both total systemic and lung exposure when a spacer was used versus no spacer. Subjects in the highest quartile had a minimal change in both total systemic and lung exposure when the spacer was used. Treatment-emergent adverse events (TEAEs) (all mild/moderate) reported by >1 subject per regimen were headache, cough, and dizziness. One subject withdrew because of TEAEs of headache and presyncope (neither considered treatment-related). IMPLICATIONS: Drug delivery can be improved for subjects with suboptimal MDI inhalation technique when using a spacer device with BGF MDI triple therapy. ClinicalTrials.gov identifier: NCT03311373.

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.

Pharmacology, toxicology and clinical safety of glycopyrrolate.

The clinical use of the anticholinergic glycopyrrolate dates back to the early 1960s when it was first approved in the U.S. Since then, oral and inhalation formulations have been developed as therapeutic agents inhibiting the muscarinic acetylcholine receptor in various indications including chronic obstructive pulmonary disease (COPD), excessive salivation, and peptic ulcers. More recently, topical formulations of glycopyrrolate (GPB, also known as glycopyrronium bromide) have gained interest as a treatment option for excessive sweating (hyperhidrosis). The U.S. Food and Drug Administration (FDA) approved the first topical glycopyrronium product for the treatment of hyperhidrosis in 2018. Glycopyrrolate, as a quaternary amine, shows minimal penetration of the blood brain barrier which limits CNS side effects. In addition, lack of phototoxicity, genotoxicity and carcinogenicity makes it suitable for chronic indications. The information on the nonclinical and clinical safety profile of glycopyrronium supporting various therapeutically approved uses has been obtained from published literature, our own data as well as summary documents issued by regulatory bodies. Collectively, these data support the conclusion that the benefits of glycopyrronium generally outweigh the risks in chronic use indications that require muscarinic receptor antagonism to provide therapeutic effects.

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.

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 (AUC0-12 ; % 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 (AUC0-12 [% 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.

Pharmacokinetics and safety of a single dose of the novel LAMA/LABA fixed-dose combination of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler, formulated using co-suspension delivery technology, in Japanese healthy subjects.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) causes significant mortality in Japan. GFF MDI is a long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination of glycopyrronium (GP) and formoterol fumarate dihydrate (FF), delivered by a metered dose inhaler (MDI) using co-suspension delivery technology, for the long-term maintenance treatment of COPD. METHODS: This randomized, Phase I, single-dose, four-treatment, four-period, crossover study (NCT02196714) examined the pharmacokinetic (PK) and safety profile of two doses of GFF MDI (28.8 µg/10 µg and 14.4 µg/10 µg) and two doses of GP MDI (28.8 µg and 14.4 µg), both formulated using co-suspension delivery technology, in healthy Japanese subjects (18-45 years of age). PK parameters included area under the curve (AUC) from 0 to 12 h (AUC0-12), AUC from 0 to the time of the last measurable plasma concentration, maximum observed plasma concentration (Cmax), and time to Cmax. Safety was monitored throughout the study. RESULTS: Plasma GP profiles were comparable between GFF MDI and GP MDI formulations containing the same GP dose. Increases in GP AUC0-12 and Cmax were generally dose proportional from 14.4 to 28.8 µg after administration of either formulation. CONCLUSIONS: The addition of FF 10 µg to GP MDI 28.8 µg or 14.4 µg in a fixed-dose combination did not appreciably alter the PK of GP, nor did an increase in GP dose from 14.4 µg to 28.8 µg in a fixed-dose combination with FF 10 µg appreciably alter the PK of formoterol. Both formulations of GFF MDI and GP MDI were well tolerated in healthy Japanese subjects. Data from this study support further evaluation of GFF MDI in Japanese patients with COPD.

Management of severe COPD exacerbations: focus on beclomethasone dipropionate/formoterol/glycopyrronium bromide.

The major determinant of the decline in lung function, quality of life, and the increased mortality risk in patients with COPD is represented by severe acute exacerbations of the disease, that is, those requiring patients' hospitalization, constituting a substantial social and health care burden in terms of morbidity and medical resource utilization. Different long-term therapeutic strategies have been proposed so far in order to prevent and/or reduce the clinical and social impact of these events, the majority of which were extrapolated from trials initially focused on the effect of long-acting muscarinic antagonist and subsequently on the efficacy of long-acting ß2-agonists in combination or not with inhaled corticosteroids. The option to employ all three classes of molecules combined, despite the limited amount of evidence in our possession, represents a choice currently proposed by international guidelines; however, current recommendations are often based mainly on observational studies or on the results of secondary outcomes in randomized controlled trials. The present narrative review evaluates the available trials that investigated the efficacy of inhaled therapy to prevent COPD exacerbations and especially severe ones, with a particular focus on beclomethasone dipropionate/formoterol/glycopyrronium bromide fixed dose combination, which is the first treatment that comprises all the three drug classes, specifically tested for the prevention of moderate and severe COPD exacerbations.

Validated ion pair chromatographic method for simultaneous determination and in vitro dissolution studies of indacaterol and glycopyrronium from inhaled capsule dosage form.

A rapid, and highly sensitive analytical method were developed for the simultaneous determination of indacaterol maleate (IND) and glycopyrronium bromide (GLY) in their inhaler capsules. Valid ion-pairing chromatographic (IPC) method was performed for separation of GLY in presence of IND using C18 column and mobile phase consisting of acetonitrile: acidified deionized water (60:40% v/v) containing 0.02% sodium dodecyl sulfate (SDS) adjusted to pH 3.0 using OPA (orthophosphoric acid) isocratically eluted at 2.0 mL/min. Quantitation was achieved with UV detection at 210 nm. Cyproheptadine was used as an internal standard. The retention times were 1.9 and 2.5 min for IND, and GLY, respectively. For the IPC method, the calibration graphs were linear in the range of 0.66-66.0 µg/mL for IND and 0.3-30.0 µg/mL for GLY. The proposed method are rapid, reproducible (R.S.D. <2.0%) and achieves satisfactory resolution between IND and GLY (resolution factor = 4.23). The mean recoveries of the analytes in their inhaler capsule were satisfactory. It was applied successfully to in vitro dissolution testing using Franz diffusion cell and extended to a content uniformity test consistent with the United States Pharmacopoeia (USP) guidelines and were found to be precise and accurate for the capsules studied with acceptance value of 4.53 and 1.39 for IND and GLY, respectively.

Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease.

Long-acting muscarinic antagonists (LAMAs), along with long-acting ß2-agonists (LABAs), are the mainstay for treatment of patients with COPD. Glycopyrrolate, or glycopyrronium bromide, like other LAMAs, inhibits parasympathetic nerve impulses by selectively blocking the binding of acetylcholine to muscarinic receptors. Glycopyrrolate is unusual in that it preferentially binds to M3 over M2 muscarinic receptors, thereby specifically targeting the primary muscarinic receptor responsible for bronchoconstriction occurring in COPD. Inhaled glycopyrrolate is slowly absorbed from the lungs and rapidly eliminated from the bloodstream, most likely by renal excretion in its unmetabolized form, limiting the potential for systemic adverse events. Inhaled glycopyrrolate is a fast-acting, efficacious treatment option for patients with moderate-severe COPD. It improves lung function, reduces the risk of exacerbations, and alleviates the symptoms of breathlessness, which in turn may explain the improvement seen in patients' quality of life. Inhaled formulations containing glycopyrrolate are well tolerated, and despite being an anticholinergic, few cardiovascular-related events have been reported. Inhaled glycopyrrolate is thus of value as both monotherapy and in combination with other classes of medication for maintenance treatment of COPD. This review covers the mechanism of action of inhaled glycopyrrolate, including its pharmacokinetic, pharmacodynamic, and safety profiles, and effects on mucus secretion. It also discusses the use of inhaled glycopyrrolate in the treatment of COPD, as monotherapy and in fixed-dose combinations with LABAs and inhaled corticosteroid-LABAs, including a triple therapy recently approved in Europe.

Safety and pharmacokinetics of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) in healthy adult subjects of Japanese descent.

INTRODUCTION: BGF MDI, a budesonide, glycopyrronium, and formoterol fumarate dihydrate triple fixed-dose combination metered dose inhaler formulated using co-suspension delivery technology, is currently in Phase III global development for chronic obstructive pulmonary disease. METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, ascending-dose, crossover study to assess the safety and pharmacokinetic profiles of two doses of BGF MDI in healthy adult subjects of Japanese descent (NCT02197975). Safety assessments included monitoring for adverse events (AEs). Pharmacokinetic parameters were assessed following a single dose and 7-days chronic dosing with BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg. RESULTS: Twenty subjects were randomized and included in the safety and pharmacokinetic populations; mean age 29.7 years; 65% male; and mean body mass index of 21.9 kg/m2. The incidences of treatment-emergent AEs (TEAEs) were similar between treatments. All the TEAEs were mild to moderate in severity. Budesonide area under the plasma concentration-time curve from 0 to 12 h (AUC0-12) and maximum observed plasma concentration (Cmax) values were approximately double for the higher dose of BGF MDI compared with the lower dose on Day 1 and also following chronic dosing on Day 8. Glycopyrronium and formoterol AUC0-12 and Cmax values on Day 8 were comparable between the two doses of BGF MDI. DISCUSSION: Both doses of BGF MDI were well tolerated in healthy subjects of Japanese descent and the systemic exposure to budesonide was dose proportional for BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg. The safety and pharmacokinetics for BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg in Japanese subjects were comparable to data from previous studies in Western populations, which suggests that the safety and efficacy profile of BGF MDI should be similar in Western and Japanese subjects.

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.

The pharmacokinetics of three doses of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler compared with active controls: A Phase I randomized, single-dose, crossover study in healthy adults.

The budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) is an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination formulated with innovative co-suspension delivery technology that is in clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, Phase I, single-dose, six-treatment, four-period, crossover study (NCT01980615) examined the pharmacokinetic (PK) and safety profile of three doses of BGF MDI (320/14.4/10 µg [equivalent to budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 µg], 160/14.4/10 µg and 80/14.4/10 µg), two doses of a budesonide/formoterol fumarate dihydrate fixed-dose combination (BUD/FORM MDI 320/9 µg and 160/9 µg; not using co-suspension delivery technology) and a glycopyrronium/formoterol fumarate dihydrate co-suspension delivery technology MDI (GFF MDI 14.4/10 µg) in healthy volunteers (18-45 years of age). PK parameters included area under the plasma concentration-time curve from 0 to 12 h (AUC0-12), AUC up to the last measurable concentration (AUC0-t), maximum plasma concentration (Cmax) and time to maximum plasma concentration (tmax). Safety was monitored throughout the study. Of 84 subjects randomized, 76 completed the study. BGF MDI 320/14.4/10 µg was bioequivalent to BUD/FORM MDI 320/9 µg for budesonide for Cmax, AUC0-12 and AUC0-t (primary objective). Dose proportionality was observed for the budesonide component between BGF MDI 80/14.4/10 µg and BGF MDI 160/14.4/10 µg, and between BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg. Systemic exposure to glycopyrronium and formoterol after BGF MDI 320/14.4/10 µg treatment was similar to GFF MDI 14.4/10 µg. The rate of adverse events was 3.7-17.9% across treatments without any serious adverse events. In conclusion, BGF MDI 320/14.4/10 µg had a similar budesonide PK profile to BUD/FORM MDI 320/9 µg. No PK drug-drug interactions were observed when budesonide was added to glycopyrronium and formoterol fumarate dihydrate. These data support the use of budesonide 320 µg and 160 µg in future clinical trials of BGF MDI in COPD.

Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology.

This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10µg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6µg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0µg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with 99mTc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.