Journal article
Subject-Specific Whole-Lung CFPD Coupled with PBPK/PD to Predict Inhaled Bronchodilator Response in Asthmatic and Healthy Subjects
Journal of aerosol science, Vol.194, 106784
05/2026
DOI: 10.1016/j.jaerosci.2026.106784
Abstract
Accurate prediction of bronchodilator performance remains challenging. We present a coupled computational fluid and particle dynamics (CFPD) and physiologically-based pharmacokinetic /pharmacodynamics (PBPK/PD) framework that leverages subject-specific CT-derived airway trees and airflow distributions to model regional lung exposure and the resulting clinical effect, quantified as the change in Forced Expiratory Volume in 1 second (ΔFEV1). Data from six asthmatic and ten healthy subjects were analyzed. CFPD simulations predicted subject-specific airflow and drug deposition by airway generation for inhalation of 400 μg albuterol using a metered dose inhaler (MDI) and a dry powder inhaler (DPI). The deposited dose was input into the PBPK model at the epithelial lining fluid (ELF) to predict drug concentrations in plasma and tissues. The PD model predicted ΔFEV1 at the subepithelium effect-site. Two key observations emerged. First, MDI use shifted the inhaled dose toward the respiratory region, whereas DPI delivery resulted in greater deposition in generations G2-G5. Second, asthmatic subjects exhibited higher resistance than healthy subjects in generations G5-G10, resulting in larger ΔFEV1. Fitted PD model parameters, yielded a half-maximal effective concentration (EC50 =1.1±0.07 nM) and Hill slope (n =1.6±0.1), with R2 = 0.98. In summary, we developed a subject-specific coupled CFPD-PBPK/PD framework to predict inhaled albuterol exposure in plasma and ELF, as well as the resulting ΔFEV1 clinical response. This approach has the potential to inform inhaler selection, optimize dosing strategies, and enable disease-specific inhalational therapies. The present study was limited to male subjects, and future work should extend the framework to include sex-specific physiological differences.
•Albuterol transport and deposition were simulated in imaging-based subject-specific asthmatic and healthy airways.•Plasma and subepithelial albuterol concentrations were predicted across subject cohorts.•MDI shifts dose to the respiratory zone, whereas DPI deposits more in proximal conducting airways.•Subepithelial effect-site concentrations in generations G5-G10 closely matched observed ΔFEV1.
Details
- Title: Subtitle
- Subject-Specific Whole-Lung CFPD Coupled with PBPK/PD to Predict Inhaled Bronchodilator Response in Asthmatic and Healthy Subjects
- Creators
- Prathish K. Rajaraman - University of IowaXuan Zhang - University of IowaAlejandro P. Comellas - University of IowaEric A. Hoffman - University of IowaChing-Long Lin - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of aerosol science, Vol.194, 106784
- DOI
- 10.1016/j.jaerosci.2026.106784
- ISSN
- 0021-8502
- eISSN
- 1879-1964
- Publisher
- Elsevier Ltd
- Grant note
- NIH: R01-HL168116 FDA: U01-FD005837, P30 ES005605, ED P116S210005 National Institutes of Health (NIH)
This work was supported in part by NIH R01-HL168116, FDA U01-FD005837, NIH P30 ES005605, and ED P116S210005. This manuscript is the result of funding in whole or in part by the National Institutes of Health (NIH) . It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH.
- Language
- English
- Electronic publication date
- 03/23/2026
- Date published
- 05/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Pulmonary, Critical Care, and Occupational Medicine; ICTS; IIHR--Hydroscience and Engineering; Mechanical Engineering; Internal Medicine
- Record Identifier
- 9985149087002771
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