Assessment Of Safety And Pharmacokinetic Profile Of A Novel Fixed Combination Of Glycopyrrolate And Formoterol HFA MDI In Healthy Volunteers

Abstract

Rationale: This first-inhuman study provided safety and pharmacokinetic (PK) data on a novel fixed dose combination of Glycopyrrolate and Formoterol Fumarate metered dose inhaler (MDI). Pearl's novel porous particle based suspension technology allows better targeting of drugs to the airways via pressurized metered dose inhaler (MDI), and enables the development of combination products with improved physical stability, content uniformity, and aerodynamic size distribution similarity across the combination drug components. The objective of this study was to provide safety and PK evidence in support of further clinical studies in patients with COPD. Methods: Study PT0030901 was a randomized, double-blind, single-dose, 4-period crossover, single-center study in healthy subjects that evaluated a single administration of 4 inhaled treatments: glycopyrrolate 72 µg (GP), formoterol fumarate 9.6 µg (FF), the fixed combination GP/FF from a single MDI, and the loose combination of GP + FF administered from two separate MDIs. At each treatment visit, subjects were assessed for 12 hours after dosing. There was a minimum 7 day washout period between treatments. Evaluations included adverse events (AEs), dry mouth and tremor assessments, hematology, clinical chemistry, vital signs, 12-lead electrocardiograms (ECG), spirometry, physical examinations, and PK parameters. Results: Sixteen subjects (11 females, 5 males), average age 27 years (range 19 to 47), were enrolled with 13 subjects completing all treatment periods. No important safety trends or signals were noted for GP/FF MDI fixed dose combination in terms of AEs, changes in serum potassium or other laboratory values, vital signs, ECGs, or spirometry parameters. Conclusions: The novel GP/FF MDI fixed dose combination was safe and well-tolerated, with a safety profile similar to that observed with the components administered individually or at the same time as a loose combination. These safety findings support further evaluation of GP/FF MDI in patients with COPD. Conclusions  In this healthy volunteer study, the combination of 72 µg of glycopyrrolate and 9.6 µg of formoterol fumarate [administered as a fixed combination (GP/FF MDI) and as a loose combination from two separate inhalers (GP MDI + FF MDI)] was observed to be safe and well tolerated with a similar safety profile to that of GP MDI and FF MDI administered alone.  Administration of drug as a loose or fixed combination resulted in similar PK profiles for GP; similar findings were observed for FF.  The data from this study support the further evaluation of GP/FF MDI in patients with COPD.

Cosuspensions of Microcrystals and Engineered Microparticles for Uniform and Efficient Delivery of Respiratory Therapeutics from Pressurized Metered Dose Inhalers

“…In addition to the formulations presented above, several other drugs indicated for the treatment of asthma or COPD, including salmeterol xinafoate, fluticasone propionate at doses up to 150 μg, tiotropium bromide, and budesonide were also rapidly and successfully formulated using the cosuspension approach (results not shown). Cosuspension pMDI for the treatment of COPD have been tested in several clinical studies to date, − including dose ranging studies of FF and GP cosuspension pMDIs in COPD patients, and studies of the GP/FF combination in healthy volunteers, to assess safety and efficacy of the individual agents and the combination.…”