iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes

Bäckman, Per; Cabal, Antonio; Clark, Andrew R.; Ehrhardt, Carsten; Forbes, Ben; Hastedt, Jayne E.; Hickey, Anthony; Hochhaus, Guenther; Jiang, Wenlei; Kassinos, Stavros C.; Kuehl, Philip J.; Prime, David; Son, Yoen-Ju; Teague, Simon P.; Tehler, Ulrika; Wylie, Jennifer

doi:10.1021/acs.molpharmaceut.2c00112

Cited by 15 publications

(15 citation statements)

References 27 publications

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“…Three hundred modeling simulations were generated using a range of values representative of those for inhaled drugs as input parameters for solubility, regional dose, and P eff . The parameters used in the modeling are summarized in Table with full details available in the iBCS 2 publication describing mechanistic modeling of pulmonary availability of inhaled drugs …”

Section: Methodsmentioning

confidence: 99%

“…This insight will inform mitigation strategies that can be used in drug discovery to design inhaled drug candidates with reduced product development risks. The underlying philosophy for establishing an iBCS and the model underpinning its application have been reported previously. ,, This publication provides a synopsis of the methodology used to generate a classification system for inhaled medicines, critiques the resulting approach to classification, and for the first time defines the iBCS classes quantitatively according to the dose number and permeability before evaluating the iBCS for its ability to categorize marketed inhaled drugs using data from the literature.…”

Section: Introductionmentioning

confidence: 99%

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iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products

Hastedt,

Bäckman,

Cabal

et al. 2023

Mol. Pharmaceutics

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In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products

Hastedt,

Bäckman,

Cabal

et al. 2023

Mol. Pharmaceutics

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“…In 2015, a workshop cosponsored by the American Association of Pharmaceutical Sciences (AAPS), US FDA, and USP was held to address the possibility of developing an inhaled biopharmaceutical classification system (iBCS) (Bäckman P. et al, 2022;Hastedt J.E. et al, 2016;.…”

Section: Inhaled Biopharmaceutical Classification Systemmentioning

confidence: 99%

“…These differences suggest that alternate or additional metrics must be adopted when developing an iBCS. Considerations for developing an iBCS include lung physiology, regional aerosol deposition, clearance mechanisms, particle dissolution, permeability, and absorption (Bäckman P. et al, 2022;Frohlich E., 2019;Hastedt J.E. et al, 2016;.…”

Section: Inhaled Biopharmaceutical Classification Systemmentioning

confidence: 99%

Performance Testing for Dry Powder Inhaler Products: Towards Clinical Relevance

Maloney

Mecham

Hickey

2023

KONA

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It is well established that the critical performance metrics for aerosol products are aerodynamic particle size distribution (APSD) and delivered dose uniformity (DDU). In broad terms, these performance characteristics dictate the efficiency and reproducibility with which an aerosol is administered clinically. However, these properties alone do not support in-vitro, in-vivo correlations. There have been numerous publications attempting to more directly link product performance testing to physiological relevance or further to draw direct correlations of relevance to bioequivalence testing for the development of generic products. While these novel methods have been employed in product development activity, their suitability for compendial testing has yet to be established. This paper explores the potential to establish biologically relevant compendial standards for dry powder inhaler products while maintaining accuracy and reproducibility of data collected to support the quality and performance of the product.

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“…Its evaluation effectiveness has been recognised by the national drug regulatory agencies and has become an important part of being considered in the review and approval process (9,10). The PBPK model established according to the drug's physicochemical properties and physiological characteristics can be used to predict the PK behaviour of the drug in vivo and has been widely used to assist the development of oral products (11)(12)(13). However, there are few applications in the field of inhalation products.…”

Section: Introductionmentioning

confidence: 99%

Bioequivalence study of ipratropium bromide inhalation aerosol using PBPK modelling

Zhang

Wu²,

Liu³

et al. 2023

Front. Med.

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AimsSystemic pharmacokinetic (PK) studies can reflect the overall exposure of orally inhaled drug Products (OIDPs) in the blood after inhalation into the lung and can be used to evaluate the bioequivalence of test and reference products. The aim of this article is: (1) to study the PK characteristics and bioequivalence of ipratropium bromide (IB) inhalation aerosol, reference and test products in healthy Chinese subjects; (2) to establish a physiologically based pharmacokinetic (PBPK) model and verify the accuracy of the model in predicting bioequivalence; (3) attempt to use the model to predict the regional distribution of particles in the lung after inhalation, and discuss the effect of gastrointestinal drug absorption of IB on systemic exposure.MethodsThe study involved two clinical studies. Clinical study-1 (registration number: CTR20201284) was used with non-clinical data to construct and validate a PBPK model in the B2O simulator, a web-based virtual drug development platform. This model assessed different test and reference products’ bioequivalence. Results were compared to a second clinical study (Clinical study-2: registration number CTR20202291). The particles’ regional distribution in the lung and the gastrointestinal absorption effect on systemic exposure were discussed based on the simulation results.ResultsThe established PBPK model successfully simulated the in vivo PK characteristics of IB inhalation aerosol, with r2 close to 1. Gastrointestinal absorption had a negligible effect on systemic exposure. Particles accumulated in the alveolar area were cleared within an hour, followed by particles in the bronchioles and bronchi.ConclusionThis model provided a reliable method for exploring the correlation between in vitro and in vivo PK studies of IB inhalation aerosols. According to the simulation results, the test and reference products were bioequivalent.

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iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes

Cited by 15 publications

References 27 publications

iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products

iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products

Performance Testing for Dry Powder Inhaler Products: Towards Clinical Relevance

Bioequivalence study of ipratropium bromide inhalation aerosol using PBPK modelling

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