Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

Hochhaus, Günther; Chen, Mong-Jen; Kurumaddali, Abhinav; Schilling, Uta; Jiao, Yuanyuan; Drescher, Stefanie K.; Amini, Elham; Berger, S. M.; Kandala, Bhargava; Tabulov, Christine; Shao, Jiahao; Seay, Brandon; Abu-Hasan, Mutasim; Baumstein, Sandra; Winner, Lawrence H.; Shur, Jagdeep; Price, Robert; Hindle, Michael; Wei, Xiangyin; Carrasco, Cynthia; Sandell, Dennis; Oguntimein, Oluwamurewa; Kinjo, Minori; Delvadia, Renishkumar; Saluja, Bhawana; Lee, Sau L.; Conti, Denise S.; Bulitta, Jürgen B.

doi:10.1208/s12248-021-00569-x

Cited by 13 publications

(15 citation statements)

References 35 publications

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“…With this reduced solubility, the dissolution profiles of particles deposited on stages 2, 4, and 6 were more distinguishable ( Figure 10 ) than those obtained with the higher-solubility medium. Our results agree with those of Liu et al [ 36 ], who also reported the masking of particle size differences when the dissolution medium provided higher solubilities The need for lower-solubility conditions was also indicated within simulations for polydisperse systems ( Figure 10 C,D) and the three experimental DPI formulations [ 23 ] for which the dissolution behavior differed, although MMAD estimates differed only slightly ( Figure 11 ).…”

Section: Discussionsupporting

confidence: 91%

“…Utilizing the described dissolution setup, and using the lower-solubility Tween 80 ® (0.5%) as dissolution medium, dissolution profiles of the three investigational FP-DPI formulations with different PSDs [ 23 ] were compared with the transfer rate of dissolved FP ( Figure 11 ). The results confirmed the sensitivity of the selected method to detect differences in MMAD.…”

Section: Resultsmentioning

confidence: 99%

“…Three previously described investigational capsule-based DPI formulations of fluticasone propionate (Formulation A, B and C; 100 µg/capsule [ 23 ]) contained the same batch of fluticasone propionate particles, but differed in lactose content and composition, resulting in different median mass aerodynamic diameters (MMAD). Capsules were delivered via a DPI Monohaler 8 ® device (Plastiape, Milan, Italy).…”

Section: Methodsmentioning

confidence: 99%

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Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

et al. 2021

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The aim of this study was to further evaluate and optimize the Transwell® system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose fraction through an anatomical mouth/throat model, resulting in a more uniform presentation of drug particles during the subsequent dissolution test. The method differed from previously published procedures by (1) using a 0.4 µm polycarbonate (PC) membrane, (2) stirring the receptor compartment, and (3) placing the drug-containing side of the filter paper face downwards, towards the PC membrane. A model developed in silico, paired with the results of in vitro studies, suggested that a dissolution medium providing a solubility of about 5 µg/mL would be a good starting point for the method’s development, resulting in mean transfer times that were about 10 times longer than those of a solution. Furthermore, the model suggested that larger donor/receptor and sampling volumes (3, 3.3 and 2 mL, respectively) will significantly reduce the so-called “mass effect”. The outcomes of this study shed further light on the impact of experimental conditions on the complex interplay of dissolution and diffusion within a volume-limited system, under non-sink conditions.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

et al. 2021

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“…Additionally, a measurement of their systemic exposure may not reflect the local PK of the drug after administration, which may be key to its efficacy and duration of action. Recently, however, Hochhaus et al reported gathering pulmonary performance characteristics such as drug residence time and regional lung deposition from PK results with fluticasone propionate which may influence the use of PK data in bioequivalent submissions in the future [ 62 ].…”

Section: Current Regulation and Official Methodologies For Inhaled Bioequivalencementioning

confidence: 99%

“…These models can result in differences in deposition from one another but generally have significant increases in IVIVC compared to the USP induction port [ 62 ]. Although realistic models such as OPC or VCU appear to have better performance with regard to representing the deposition in the mouth-throat than the other models, in at least one study, results from the OPC, VCU and AIT were averaged together to accommodate these differences [ 62 , 83 ]. From those two, the OPC model is the only mouth-throat model with clinical validation [ 79 ].…”

Section: Alternative Methods For Bioequivalencementioning

confidence: 99%

Innovating on Inhaled Bioequivalence: A Critical Analysis of the Current Limitations, Potential Solutions and Stakeholders of the Process

Gallegos-Catalán

Warnken²,

Bahamondez-Canas

et al. 2021

Pharmaceutics

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Orally inhaled drug products (OIDPs) are an important group of medicines traditionally used to treat pulmonary diseases. Over the past decade, this trend has broadened, increasing their use in other conditions such as diabetes, expanding the interest in this administration route. Thus, the bioequivalence of OIDPs is more important than ever, aiming to increase access to affordable, safe and effective medicines, which translates into better public health policies. However, regulatory agencies leading the bioequivalence process are still deciding the best approach for ensuring a proposed inhalable product is bioequivalent. This lack of agreement translates into less cost-effective strategies to determine bioequivalence, discouraging innovation in this field. The Next-Generation Impactor (NGI) is an example of the slow pace at which the inhalation field evolves. The NGI was officially implemented in 2003, being the last equipment innovation for OIDP characterization. Even though it was a breakthrough in the field, it did not solve other deficiencies of the BE process such as dissolution rate analysis on physiologically relevant conditions, being the last attempt of transferring technology into the field. This review aims to reveal the steps required for innovation in the regulations defining the bioequivalence of OIDPs, elucidating the pitfalls of implementing new technologies in the current standards. To do so, we collected the opinion of experts from the literature to explain these trends, showing, for the first time, the stakeholders of the OIDP market. This review analyzes the stakeholders involved in the development, improvement and implementation of methodologies that can help assess bioequivalence between OIDPs. Additionally, it presents a list of methods potentially useful to overcome some of the current limitations of the bioequivalence standard methodologies. Finally, we review one of the most revolutionary approaches, the inhaled Biopharmaceutical Classification System (IBCs), which can help establish priorities and order in both the innovation process and in regulations for OIDPs.

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Considerations for the Forced Expiratory Volume in 1 Second‐Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products

Lee

Feng

Conti

et al. 2022

Clin Pharma and Therapeutics

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Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards’ current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product‐associated complexities of OIDPs, the FDA currently uses an aggregate weight‐of‐evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV1) are often the recommended clinical endpoints. However, the use of FEV1 can pose a challenge due to its large variability and a relatively flat dose‐response relationship for most OIDPs. The utility of applying dose‐scale analysis was also investigated by the FDA but often not recommended, due to either flat dose‐response relationships or insufficient clinical study data. As a potential way to reduce sample size, we found adapting covariate analysis only explained a limited portion of the variation based on further investigation. The FDA continues to develop alternative methods to make BE assessment of OIDPs more cost‐ and time‐efficient. Prospective generic drug applicants and academia are encouraged to participate in this effort by proposing new approaches in pre‐abbreviated new drug application meeting requests and collaborating in the form of grants and contracts under the Generic Drug User Fee Amendments (GDUFA) Regulatory Science and Research Program.

show abstract

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

Cited by 13 publications

References 35 publications

Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

Innovating on Inhaled Bioequivalence: A Critical Analysis of the Current Limitations, Potential Solutions and Stakeholders of the Process

Considerations for the Forced Expiratory Volume in 1 Second‐Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products

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