Dataset Information

Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

ABSTRACT: This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 µm, B-3.8 µm and C-3.7 µm; total single dose: 500 µg). Systemic disposition parameter estimates were obtained from published pharmacokinetic data after intravenous dosing to improve robustness. A biphasic pulmonary absorption model, with mucociliary clearance from the slower absorption compartment, and three systemic disposition compartments was most suitable. Rapid absorption, presumably from peripheral lung, had half-lives of 6.9 to 14.6 min. The peripherally deposited dose (12.6 µg) was significantly smaller for formulation A-4.5 µm than for the other formulations (38.7 and 39.3 µg for B-3.8 µm and C-3.7 µm). The slow absorption half-lives ranged from 6.86 to 9.13 h and were presumably associated with more central lung regions, where mucociliary clearance removed approximately half of the centrally deposited dose. Simulation-estimation studies showed that a biphasic absorption model could be reliably identified and that parameter estimates were unbiased and reasonably precise. Bioequivalence assessment of population pharmacokinetics derived central and peripheral lung doses suggested that formulation A-4.5 µm lacked bioequivalence compared to the other formulations both for central and peripheral doses. In contrast, the other fomulations were bioequivalent. Overall, population pharmacokinetics holds promise to provide important insights into the pulmonary fate of inhalation drugs, which are not available from non-compartmental analysis. This supports the assessment of the pulmonary bioequivalence of fluticasone propionate inhaled formulations through pharmacokinetic approaches, and may be helpful for discussions on evaluating alternatives to clinical endpoint studies.

SUBMITTER: Drescher SK

PROVIDER: S-EPMC10686290 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

Drescher Stefanie K SK Jiao Yuanyuan Y Chen Mong-Jen MJ Kurumaddali Abhinav A Shao Jie J Amini Elham E Hochhaus Günther G Bulitta Jürgen B JB

Pharmaceutical research 20230420 5

This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 µm, B-3.8 µm and C-3.7 µm; total single dose: 500 µg). Systemic disposition parameter estimates were obtained from published pharmacokinetic data after intravenous dosing to improve robustness. A biphasic pulmonary absorption model, with mucociliary clearance from the slower abso ...[more]

PMID: 37081302

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Project description:BACKGROUND:Easyhaler® dry powder inhaler (DPI) containing salmeterol and fluticasone propionate was developed for the treatment of asthma and chronic obstructive pulmonary disease. Three different Salmeterol/fluticasone Easyhaler test products (Orion Pharma, Finland) were compared against the reference product Seretide® Diskus® DPI (GlaxoSmithKline, United Kingdom) to study whether any of the test products are bioequivalent with the reference. METHODS:Open and randomized pharmacokinetic four-period crossover study on 65 healthy volunteers was performed in a single center to compare the lung deposition and total systemic exposure of salmeterol and fluticasone propionate after administration of single doses (two inhalations of 50/500??g/inhalation strength) in fasting conditions. Blood samples were drawn before dosing and at frequent time points between 2 minutes and 34 hours after dosing for determination of drug concentrations. The primary variables for total systemic exposure and lung deposition of fluticasone propionate were maximum concentration of the concentration-time curve (Cmax) and area under the concentration-time curve from time zero to the last sample with quantifiable concentration (AUCt). For salmeterol, the primary variables for total systemic exposure were Cmax and AUCt and for lung deposition Cmax and AUC up to 30 minutes after study treatment administration (AUC30min). RESULTS:One of the Easyhaler test products met all the criteria for bioequivalence with the reference. The 96.7% confidence intervals (CIs) for the test/reference ratios of fluticasone propionate Cmax and AUCt were 0.9901-1.1336 and 0.9448-1.0542, respectively. Ninety percent CIs for salmeterol Cmax, AUC30min, and AUCt ratios were 1.0567-1.2012, 1.0989-1.2255, and 1.0769-1.1829, respectively. Median salmeterol time to maximum concentration (tmax) was 4.0 minutes. Median fluticasone propionate tmax was from 1.5 to 2.0 hours. Terminal elimination half-life was 11 hours for salmeterol and 9-10 hours for fluticasone propionate. CONCLUSIONS:Salmeterol/fluticasone Easyhaler was shown to be bioequivalent with the reference product.

Project description:Effective strategies against the spread of respiratory viruses are needed, as tragically demonstrated during the COVID-19 pandemic. Apart from vaccines, other preventive or protective measures are necessary: one promising strategy involves the nasal delivery of preventive or protective agents, targeting the site of initial infection. Harnessing the immune system's ability to produce specific antibodies, a hyperimmune serum, collected from an individual vaccinated against SARS-CoV-2, was formulated as a dry powder for nasal administration. The selection of adequate excipients and process are key to maintaining protein stability and modulating the aerodynamic properties of the powders for reaching the desired respiratory regions. To this end, a hyperimmune serum was formulated with trehalose and mannitol as bulking agents during spray drying, then the ability of the redissolved immunoglobulins to bind Spike protein was verified by ELISA; foetal bovine serum was formulated in the same conditions as a reference. Moreover, a seroneutralization assay against SARS-CoV-2 pseudoviruses generated from different variants of concern was performed. The neutralizing ability of the serum was slightly reduced with respect to the starting serum when trehalose was used as a bulking agent. The powders were loaded in hypromellose capsules and aerosolized employing a nasal insufflator in an in vitro model of the nasal cavity connected to a Next Generation Impactor. The analysis of the powder distribution confirmed that all powders were inhalable and could target, at the same time, the upper and the lower airways. This is a preliminary proof-of-concept that this approach can constitute an effective strategy to provide broad coverage and protection against SARS-CoV-2, and in general against viruses affecting the airway. According to blood availability from donors, pools of hyperimmune sera could be rapidly formulated and administered, providing a simultaneous and timely neutralization of emerging viral variants.

Project description:Background: Dry powder inhalers (DPIs) require patients to impart sufficient energy through inhalation to ensure adequate dose emission, medication deaggregation, and resultant particle sizes suitable for lung deposition. There is an ongoing debate regarding the level of inspiratory effort, and therefore inspiratory flow rate, needed for optimal dose delivery from DPIs. Materials and Methods: The delivered dose (DD) and fine particle fraction (FPF) for each component of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg and FF/UMEC/VI 200/62.5/25 μg ELLIPTA DPIs were assessed at flow rates of 30, 60, and 90 L/min. Electronic lung (eLung) (eLung; an electronic breathing simulator) assessments were conducted to replicate inhalation profiles representing a wide range of inhalation parameters and inhaled volumes achieved by patients with chronic obstructive pulmonary disease (COPD) or asthma of all severity levels. Timing and duration of dose emission were assessed using a particle detector located at the entrance of an anatomical throat cast attached to the eLung. Results: During DD assessment, a mean of >80% of the nominal blister content (nbc) was emitted from the ELLIPTA DPI at all flow rates. In Next Generation Impactor assessments, the observed mean DD across flow rates for FF/UMEC/VI 100/62.5/25 μg ranged from 85.9% to 97.0% of nbc and 84.0% to 93.5% for FF/UMEC/VI 200/62.5/25 μg. In eLung assessments, 82.8% to 95.5% of nbc was delivered across the PIF range, 43.5 to 129.9 L/min (COPD), and 85.1% to 92.3% across the PIF range, 67.4 to 129.9 L/min (asthma). The FPF (mass <5 μm; % nbc) for each component was comparable across all flow rates and inhalation profiles. Dose emission timings indicated that near-complete dose emission occurs before reaching PIF. Conclusions: Dose delivery assessments across all flow rates and inhalation profiles indicate that patients with all severity levels of COPD or asthma can achieve the required inspiratory effort for efficient delivery of all components of FF/UMEC/VI from the ELLIPTA DPI. Dose emission profiles suggest rapid and near-complete dose delivery from the ELLIPTA DPI before reaching PIF.

Project description:Background: Wixela Inhub is a generic version of Advair Diskus recently approved by the U.S. Food and Drug Administration. The Inhub inhaler delivers fluticasone propionate (FP)/salmeterol in a dry powder formulation. The goals of our studies were to demonstrate that the Inhub inhaler can be used by representative end users and confirm the robustness of the Inhub inhaler. Methods: Study 1: A nondosing usability assessment, the device orientation study, confirmed that intended users (represented by patients diagnosed with asthma or chronic obstructive pulmonary disease [COPD] who were naive to dry powder inhalers and current Advair Diskus users) could use the Inhub inhaler safely and effectively. Subjects were provided with an Inhub inhaler in commercial packaging, including instructions for use, and were asked to undertake three dose simulations using the inhaler. Subjects were encouraged to interact with this new drug delivery device as they would at home. Subjects were not provided with training on the use of the device. Subjects were observed interacting with the Inhub inhaler, and those who currently use Diskus were also observed interacting with the Diskus to determine whether their mental model of the use of Diskus impacted their interaction with the Inhub device, this assessment was not a primary outcome of the study. Study 2: This is an open-label clinical study to confirm the robustness of the Inhub inhaler after at home patient use. Subjects diagnosed with asthma or COPD were provided Inhub inhaler training and subsequently self-administered 3 weeks of twice daily doses of Wixela Inhub 250 μg FP/50 μg salmeterol in the home environment. The Inhub inhalers were returned to the investigator after ∼3 weeks of outpatient use for in vitro tests on the drug remaining in each inhaler. Results: Study 1 enrolled 110 subjects, and all completed the study. Most subjects (100/110) held the Inhub inhaler in the correct orientation and of those who did not, 9 still achieved a peak inhalation flow rate of ≥30 L/min and a total inhaled volume of ≥1 L, thus meeting the requirements of the study success criteria. In Study 2, 111 pediatric, adult, and elderly subjects with asthma or COPD received the study drug. After ∼3 weeks of outpatient use of the Inhub inhaler by subjects, comprehensive in vitro testing demonstrated that the FP and salmeterol pharmaceutical performance in the Inhub inhaler was preserved. Conclusions: The majority of subjects demonstrated safe and effective use of the Inhub inhaler. In vitro testing and inspections confirmed the robustness of the Inhub inhaler after outpatient use. Clinical trial registration number: NCT02474017.

Dataset Information

Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

Publications

Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

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