Pharmacokinetics of budesonide and formoterol administered via a series of single‐drug and combination inhalers: four open‐label, randomized, crossover studies in healthy adults

Eklund, Annika; Tronde, Ann; Johannes-Hellberg, Ingegerd; Gillen, Michael; Borgström, Lars

doi:10.1002/bdd.622

Cited by 20 publications

(10 citation statements)

References 42 publications

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“…[33][34][35][36][37] No PK interactions, whether due to formulation or drug-drug interactions, were observed when glycopyrronium was formulated with budesonide and formoterol in the BGF MDI fixed-dose combination using co-suspension delivery technology, based on the equivalence of PK parameters of budesonide and formoterol between BGF MDI and BFF MDI. 27,39,40 A limitation of the study was the collection of blood samples for analysis of PK parameters only up to 12-hours after dosing. 38 The absence of any drug-drug interactions in the current study among the individual components of BGF MDI incorporated into the triple fixed-dose combination is aligned with the consistent drug delivery seen across mono and dual bronchodilator MDI formulations incorporating co-suspension delivery technology.…”

Section: Discussionmentioning

confidence: 99%

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

Maes

DePetrillo²,

Siddiqui

et al. 2018

Clinical Pharm in Drug Dev

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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 ; % 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 [% 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.

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Section: Discussionmentioning

confidence: 99%

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

Maes

DePetrillo²,

Siddiqui

et al. 2018

Clinical Pharm in Drug Dev

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“…[6] The definition of a threshold concentration requires the performance of different administration studies in healthy subjects to assess the urinary levels of the compound after administration of allowed doses. [7][8][9][10] In spite of the high number of pharmacokinetic studies of formoterol in healthy subjects [11][12][13][14] or patients with asthma or COPD, [15] few data on urinary concentrations of formoterol after inhaled administrations are available in the literature to support the threshold value defined by WADA. [16][17][18][19] The objective of this work was to evaluate the threshold concentration of formoterol recently defined by WADA by studying urinary concentrations of the compound in healthy volunteers after inhalation of the maximum allowed dose and in samples from athletes with declared inhaled administration.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the urinary threshold concentration of formoterol in sports drug testing

Ventura

Damasceno

Ramirez

et al. 2013

Drug Testing and Analysis

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The use of formoterol in sports is allowed by inhalation at the maximum recommended therapeutic dose. Recently, a threshold concentration of 30 ng.mL(-1) was defined by the World Anti-Doping Agency (WADA) to distinguish between therapeutic and forbidden use of formoterol. The objective of this work was to evaluate that threshold concentration. Concentrations of formoterol were measured in urine samples collected after administration of 18 µg of inhaled formoterol to five healthy volunteers, and in samples collected in routine doping tests belonging to athletes having declared inhaled formoterol use. Formoterol was detected up to 8 h after administration in all volunteers with concentrations up to 19.6 ng.mL(-1) . From 28 routine samples, 27 had less than 10 ng.mL(-1) of formoterol and only in one of the samples the concentration was 25 ng.mL(-1) . Therefore, administration of formoterol by inhalation at the maximum dose allowed by WADA will not produce false positive results using a threshold concentration of 30 ng.mL(-1) , and the experience up to now in routine doping tests indicates that the probability of obtaining urines with concentrations greater than 30 ng.mL(-1) is close to nil. For this reason, sports authorities should re-evaluate the need of a threshold concentration for formoterol and its practical usefulness.

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“…Studies also suggest that a LABA may enhance the inhibitory effect of an ICS on allergen-induced activation of certain inflammatory cytokines (eg, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, interleukin-1β, interleukin-2) 15,16. Specific details of the pharmacokinetic properties of budesonide and formoterol administered via pMDI have been described in detail previously 17,18…”

Section: Clinical Pharmacologymentioning

confidence: 99%

Treatment with budesonide/formoterol pressurized metered-dose inhaler in patients with asthma: a focus on patient-reported outcomes

O’Connor

2011

PROM

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In the United States, budesonide/formoterol pressurized metered-dose inhaler (pMDI) is approved for treatment of asthma in patients aged ≥12 years whose asthma is not adequately controlled with an inhaled corticosteroid (ICS) or whose disease severity clearly warrants treatment with an ICS and a long-acting β2-adrenergic agonist. This article reviews studies of budesonide/formoterol pMDI in patients with persistent asthma, with a particular focus on patient-reported outcomes (eg, perceived onset of effect, patient satisfaction with treatment, health-related quality of life [HRQL], global assessments, sleep quality and quantity), as these measures reflect patient perceptions of asthma control and disease burden. A search of PubMed and respiratory meetings was performed to identify relevant studies. In two pivotal budesonide/formoterol pMDI studies in adolescents and adults, greater efficacy and similar tolerability were shown with budesonide/formoterol pMDI 160/9 μg and 320/9 μg twice daily versus its monocomponents or placebo. In those studies, improvements in HRQL, patient satisfaction, global assessments of asthma control, and quality of sleep also favored budesonide/formoterol pMDI compared with one or both of its monocomponents or placebo. Budesonide/formoterol pMDI has a rapid onset of effect (within 15 minutes) that patients can feel, an attribute that may have benefits for treatment adherence. In summary, budesonide/formoterol pMDI is effective and well tolerated and has additional therapeutic benefits that may be important from the patient’s perspective.

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Pharmacokinetics of budesonide and formoterol administered via a series of single‐drug and combination inhalers: four open‐label, randomized, crossover studies in healthy adults

Cited by 20 publications

References 42 publications

Evaluation of the urinary threshold concentration of formoterol in sports drug testing

Treatment with budesonide/formoterol pressurized metered-dose inhaler in patients with asthma: a focus on patient-reported outcomes

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