Review

. 2023 May;12(5):560-574.

doi: 10.1002/psp4.12889. Epub 2022 Dec 20.

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report

Ross L Walenga¹, Clare Butler², Brent A Craven³, P Worth Longest⁴, Raja Mohamed⁵, Bryan Newman⁶, Bo Olsson⁷, Günther Hochhaus⁸, Bing V Li⁹, Markham C Luke⁶, Liang Zhao¹, Andrzej Przekwas¹⁰, Robert Lionberger¹¹

Affiliations

¹ Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
² Inhaled Drug Product Research and Development Division, Teva Pharmaceuticals Ireland, Waterford, Ireland.
³ Division of Applied Mechanics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
⁴ Virginia Commonwealth University, Richmond, Virginia, USA.
⁵ Novartis Healthcare Private Ltd, Sandoz Development Centre (SDC), India.
⁶ Division of Therapeutic Performance I, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
⁷ Emmace Consulting AB, Lund, Sweden.
⁸ Department of Pharmaceutics, University of Florida, Gainesville, Florida, USA.
⁹ Office of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
¹⁰ CFD Research Corporation, Huntsville, Alabama, USA.
¹¹ Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

PMID: 36330693
PMCID: PMC10196431
DOI: 10.1002/psp4.12889

Review

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report

Ross L Walenga et al. CPT Pharmacometrics Syst Pharmacol. 2023 May.

. 2023 May;12(5):560-574.

doi: 10.1002/psp4.12889. Epub 2022 Dec 20.

Authors

Affiliations

¹ Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
² Inhaled Drug Product Research and Development Division, Teva Pharmaceuticals Ireland, Waterford, Ireland.
³ Division of Applied Mechanics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
⁴ Virginia Commonwealth University, Richmond, Virginia, USA.
⁵ Novartis Healthcare Private Ltd, Sandoz Development Centre (SDC), India.
⁶ Division of Therapeutic Performance I, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
⁷ Emmace Consulting AB, Lund, Sweden.
⁸ Department of Pharmaceutics, University of Florida, Gainesville, Florida, USA.
⁹ Office of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
¹⁰ CFD Research Corporation, Huntsville, Alabama, USA.
¹¹ Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

PMID: 36330693
PMCID: PMC10196431
DOI: 10.1002/psp4.12889

Abstract

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

© 2022 Teva Pharmaceuticals Ireland, Novartis Healthcare Private Limited, India and The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

PubMed Disclaimer

Conflict of interest statement

The authors declared no competing interests for this work.

Figures

**FIGURE 1**
Flow chart illustrating the American Society of Mechanical Engineers Verification and Validation 40–2018 framework for establishing the credibility of computational modeling and simulation of medical devices.

**FIGURE 2**
Unweighted linear regression of in silico on in vivo results for the peripheral/central (P/C) ratio. O indicates healthy volunteers, and X indicates asthmatics. Reproduced from Olsson and Kassinos.

**FIGURE 3**
Elements of a computational fluid dynamics–based complete‐airway stochastic individual pathway model for comparison of regional MDI and DPI drug delivery including (a) computational models of the inhaler flow pathways and conducting airways, (b) prescribed SD and QD inhalation profiles, (c) experimentally measured particle size distributions at different tested flow rates, and (d) deposition fractions in specific airway regions as a percentage of aerosolized drug. DPI, dry powder inhaler; MDI, metered dose inhaler; MMAD, mass median aerodynamic diameter; MT, mouth–throat; Q, flow rate; QD, quick and deep; SD, slow and deep; TB, tracheobronchial. Reprinted by permission from Springer Nature: Springer Nature, Pharmaceutical Research, Comparing MDI and DPI aerosol deposition using in vitro experiments and a new stochastic individual path (SIP) model of the conducting airways Longest et al.

**FIGURE 4**
Dosing, pulmonary PK, and systemic PK following orally inhaled drug product administration. GI, gastrointestinal; PK, pharmacokinetics. Reprinted from *International Journal of Pharmaceutics*, 549, Hatipoglu MK, Hickey AJ, Garcia‐Contreras L, Pharmacokinetics and pharmacodynamics of high doses of inhaled dry powder drugs, 306–316, Copyright 2018, with permission from Elsevier.

See this image and copyright information in PMC

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Mechanistic modeling of generic orally inhaled drug products: A workshop summary report

Affiliations

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources