A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

Area of Science:

• Pharmacokinetics and Drug Disposition
• Computational Modeling
• Respiratory Drug Delivery

Background:

• Pulmonary drug disposition prediction is challenging due to lung heterogeneity and complex disposition processes.
• Current inhalation physiologically based pharmacokinetic (PBPK) models lack features to fully capture these complexities, limiting accurate local exposure prediction.

Purpose of the Study:

• To develop an advanced inhalation PBPK model that incorporates lung heterogeneity and particle size variations.
• To mechanistically simulate key pulmonary drug disposition processes for enhanced predictive accuracy.

Main Methods:

• Utilized partial differential equations to create a physiologically based pharmacokinetic (PBPK) model for inhaled drugs.
• Incorporated mechanisms for particle deposition, mucociliary clearance, and dissolution.
• Introduced computational simplifications to maintain accuracy while reducing cost.

Main Results:

• Demonstrated the model's ability to enhance understanding of pulmonary drug disposition through three case studies.
• Identified that most small airways are targetable via inhalation.
• Highlighted the risk of overdosing negating inhalation benefits.

Conclusions:

• The developed inhalation PBPK model provides a robust tool for predicting pulmonary drug disposition.
• The model can guide the design of inhaled molecules, formulations, and clinical trials.
• Offers opportunities for exploring regional drug targeting within the lungs.