Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology

Ferguson, Gary T.; Reisner, Colin; Pearle, James; DePetrillo, Paolo B.; Maes, Andrea; Martin, Ubaldo J.

doi:10.1016/j.pupt.2018.01.007

Cited by 7 publications

(5 citation statements)

References 16 publications

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“…[14,16] A recent study investigating the PK properties of inhaled glycopyrronium 50 mg in healthy Chinese subjects concluded that the glycopyrronium systemic exposure after single and 14-day once-daily dosing could be considered to be consistent across Chinese, Japanese, and white subjects. [19] Given the variability in glycopyrronium PK parameters between subjects and studies, and that higher doses of glycopyrronium than those in BGF MDI have been shown to be well tolerated, [21,22] the differences are not expected to constitute a safety concern. The clinical efficacy and tolerability of BGF MDI in patients with COPD are supported by findings from a Phase III study in patients with COPD that included patients from the United States, Canada, Japan, and China.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study

Chen

Yu³

et al. 2019

Clinical Therapeutics

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Purpose: The objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixeddose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing.Methods: This Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18e45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 mg, BGF MDI 160/14.4/10 mg, or GFF MDI 14.4/10 mg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC 0e12 , C max , and T max . Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values.Findings: Ninety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC 0e12 and C max were increased dose proportionally from BGF MDI 160/14.4/10 mg to BGF MDI 320/14.4/10 mg, respectively (single dose: AUC 0e12 , 811.8 vs 1748 h $ pg/mL; C max , 224.3 vs 459.3 pg/mL; repeated dosing: AUC 0e12 , 1250 vs 2510 h $ pg/mL; C max , 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC 0e12 and C max were similar across all treatments (single dose: AUC 0e12 , 27.20e29.40 h $ pg/mL; C max , 4.884e5.674 pg/mL; repeated dosing: AUC 0e12 , 69.49e77.08 h $ pg/mL; C max , 11.30e13.12 pg/mL) and formoterol (single dose: AUC 0e12 , 46.49e53.58 h $ pg/mL; C max 9.651e10.62 pg/mL; repeated dosing: AUC 0e12 , 81.94e85.32 h $ pg/mL; C max, 16.13e17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%e56.3%). There were no new or unexpected findings on tolerability.Implications: Overall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267. (Clin Ther. 2019;41:897e909)

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study

Chen

Yu³

et al. 2019

Clinical Therapeutics

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“…Studies have specifically examined the cardiovascular safety profile of fixed-dose combinations incorporating glycopyrronium and formoterol delivered via inhalers. These investigations have indicated that GFF therapy, administered through a metered dose inhaler utilizing Co-Suspension™ delivery technology, exhibits a favorable cardiovascular safety profile [ 27 , 28 ]. Additionally, the cardiovascular safety profiles of alternative combination therapies, such as QVA149 and budesonide/glycopyrrolate/formoterol fumarate, have also been evaluated, underscoring the importance of assessing cardiovascular effects when considering treatment options for respiratory conditions [ 29 , 30 ].…”

Section: Reviewmentioning

confidence: 99%

“…This comprehensive analysis further reaffirmed the sustained long-term safety and tolerability of GFF MDI 18/9.6 μg twice daily in subjects navigating moderate-to-very severe COPD [ 33 ]. Moreover, a study evaluating the cardiovascular safety profile of a fixed-dose combination comprising glycopyrrolate and formoterol fumarate, delivered via metered dose inhaler utilizing Co-Suspension™ delivery technology, concluded that the combination therapy was both safe and well-tolerated [ 28 ]. These findings collectively underscore the favorable long-term safety and tolerability profile of GFF therapy, reinforcing its suitability for extended use in patients managing moderate to severe COPD.…”

Section: Reviewmentioning

confidence: 99%

Comparing Glycopyrronium/Formoterol Combination Therapy With Monotherapy in Moderate-to-Severe Chronic Obstructive Pulmonary Disease (COPD): A Narrative Review

Prada,

Jadhav,

Ghewade

et al. 2024

Cureus

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Chronic obstructive pulmonary disease (COPD) imposes a significant burden on individuals and healthcare systems globally. While bronchodilators, such as glycopyrronium and formoterol, are cornerstone therapies for COPD management, combining these agents has gained attention for potentially improving outcomes compared to monotherapy. This comprehensive review aims to assess the efficacy and safety of glycopyrronium/formoterol (GFF) combination therapy versus glycopyrronium monotherapy in patients with moderate-to-severe COPD. Through a systematic evaluation of clinical trials and real-world evidence, we analyze the impact of combination therapy on lung function, symptom control, exacerbation rates, and health-related quality of life (HRQoL). Furthermore, we examine the safety profile of combination therapy, including adverse cardiovascular and respiratory events. Comparative analyses with glycopyrronium monotherapy provide insights into the relative benefits and considerations for treatment selection. Factors influencing treatment choice and future directions in COPD management are also discussed. This review underscores the potential of combination therapy in optimizing COPD treatment outcomes and highlights areas for further research and clinical practice refinement.

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“…The KRONOS study (NCT01349803) compared budesonide/glycopyrrolate/formoterol fumarate (BUD/GP/FF) pMDI with several dual therapies and found a significant improvement in FEV 1 area under the curve from 0 to 4 hours with triple therapy compared with budesonide-based dual therapies. 43 Unlike other studies of triple therapy, KRONOS did not restrict the population based on history of exacerbations. In this population, the triple therapy regimen significantly reduced exacerbation rates versus dual therapy with glycopyrrolate and formoterol pMDI, thus supporting the use of triple therapy for patients with lower exacerbation risk.…”

Section: Triple Therapy Regimens Containing Formoterolmentioning

confidence: 99%

“…46 Two studies found no effects of therapeutic and supratherapeutic dosages of glycopyrrolate/formoterol pMDI using co-suspension delivery technology on cardiovascular parameters. 43 The US FDA had concerns about high-dose formoterol based on a 2003 review of three studies that found more frequent serious asthma exacerbations in patients receiving formoterol 24 μg BID compared with those receiving placebo. 47 The FDA concluded that this finding was consistent with previously published, placebo-controlled, randomized trials of another LABA, salmeterol.…”

Section: Safety Of Inhaled Formoterol In Patients With Copdmentioning

confidence: 99%

<p>Formoterol for the Treatment of Chronic Obstructive Pulmonary Disease</p>

Tashkin

2020

COPD

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Bronchodilators, including long-acting β 2-agonists and long-acting muscarinic antagonists, are the mainstay for treatment of patients with chronic obstructive pulmonary disease (COPD) to prevent exacerbations or reduce symptoms. Formoterol is a highly selective and potent β 2-agonist that relaxes airway smooth muscle to significantly improve lung function. Inhaled formoterol works within 5 minutes of administration and provides improvements in spirometry measurements over 12 hours. The lipophilicity of formoterol allows it to form a depot within the smooth muscle to provide a prolonged duration of action. Following therapeutic doses, plasma concentrations are very low or undetectable. Determination of the pharmacokinetics of formoterol following high-dose administration to healthy volunteers revealed that the drug was rapidly absorbed and excreted unchanged in the urine with a half-life of 10 hours. Inhaled formoterol, as monotherapy or in combination with other agents, is an effective and safe treatment option for patients with moderate to severe COPD. Clinical studies have demonstrated improvements in lung function and COPD symptoms, particularly dyspnea; reductions in the risk of exacerbations; and improvement in patients' health status. The adverse event profile of inhaled formoterol is similar to that of placebo, with few adverse cardiovascular events. Formoterol is a valuable bronchodilator used in the maintenance treatment of COPD. This review describes the mechanism of action, pharmacodynamics, and pharmacokinetics of inhaled formoterol. It also reviews the results of large, randomized, controlled clinical trials that evaluated the use of formoterol as monotherapy and in combination with inhaled corticosteroids, long-acting muscarinic antagonists, and triple therapy regimens in the treatment of patients with moderate to severe COPD.

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Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology

Cited by 7 publications

References 16 publications

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study

Comparing Glycopyrronium/Formoterol Combination Therapy With Monotherapy in Moderate-to-Severe Chronic Obstructive Pulmonary Disease (COPD): A Narrative Review

<p>Formoterol for the Treatment of Chronic Obstructive Pulmonary Disease</p>

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