Models of deposition, pharmacokinetics, and intersubject variability in respiratory drug delivery

ABSTRACT

Introduction: Aerosol drug delivery to the lungs via inhalation is widely used in the treatment of respiratory diseases. The deposition pattern of inhaled particles within the airways of the respiratory tract is key in determining the initial delivered dose. Thereafter, dose-dependent processes including drug release or dissolution, clearance, and absorption influence local and systemic exposure to inhaled drugs over time.

Areas covered: Empirical correlations, numerical simulation, and in vitro airway geometries that permit improved prediction of extrathoracic and lung deposition fractions in a variety of age groups and breathing conditions are described. Efforts to link deposition models with pharmacokinetic models predicting lung and systemic exposure to inhaled drugs over time are then reviewed. Finally, new methods to predict intersubject variability in extrathoracic deposition, capturing variability in both size and shape of the upper airways, are highlighted.

Expert opinion: Recent work has been done to expand in vitro deposition experiments to a wide range of age groups and breathing conditions, to link regional lung deposition models with pharmacokinetic models, and to improve prediction of intersubject variability. These efforts are improving predictive understanding of respiratory drug delivery, and will aid the development of new inhaled drugs and delivery devices.

KEYWORDS:

• Aerosol
• deposition
• in vitro in vivo correlations
• inhaler
• intersubject variability
• lungs
• modeling
• pharmacokinetics
• simulation

Article highlights

• Empirical correlations and in vitro experiments using upper airway geometries (e.g. mouth–throat geometries) can be used to predict average upper airway and lung deposition fractions for a wide variety of age groups and breathing conditions.

• For pMDIs, physical phenomena influencing mouth–throat deposition are not fully captured by existing empirical correlations. In vitro measurements using established idealized or realistic mouth–throat geometries are preferred for estimating mouth–throat and lung deposition.

• Coupling regional lung deposition models with pharmacokinetic models allows local and systemic drug concentrations to be predicted over time, which provides a more direct link to drug efficacy and safety then does regional deposition prediction alone.

• Intersubject variability in mouth–throat deposition is influenced by both the size and the shape of the mouth–throat geometry. To rigorously predict mouth–throat deposition variability, effects of variable mouth–throat shape must be captured independently of effects of variable mouth–throat size.

• Prediction of regional exposure to inhaled drugs in diseased lungs, and prediction of intersubject and intrasubject variability in regional lung doses, both remain open research challenges.

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Declaration of interest

WH Finlay receives royalties from Copley Scientific for sales of the Alberta Idealised Throat. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.