Informing Sampling Design for Lung Distribution Studies Using a Pulmonary Population Minimal PBPK Model

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Inhaled Drug Delivery Systems
• Computational Modeling in Pharmacology

Background:

• Understanding intrapulmonary pharmacokinetics (PK) is crucial for inhaled drug development.
• Current lung sampling methods like bronchoalveolar lavage (BAL) and biopsy have limitations.
• Bronchosorption offers enhanced regional specificity and reduced quantification errors for intrapulmonary drug analysis.

Purpose of the Study:

• To develop a pulmonary population physiologically based pharmacokinetic (PBPK) model for inhaled salbutamol.
• To integrate data from BAL, biopsy, and bronchosorption techniques for improved PK predictions.
• To compare different intrapulmonary sampling strategies to optimize future study designs.

Main Methods:

• Developed a population-based minimal PBPK model using existing salbutamol PK data.
• Assessed the impact of permeability on pulmonary PK and epithelial lining fluid (ELF)-to-plasma ratios.
• Employed stochastic simulation-estimation (SSE) to evaluate single and combined sampling techniques (BAL, biopsy, bronchosorption).
• Compared uniform and staggered bronchosorption sampling strategies for drugs with varying permeability.

Main Results:

• The PBPK model estimated key parameters: lung tissue-plasma partition coefficient (Kp,u,lung) of 11.0 and effective permeability (Peff) of 0.543 m/h for salbutamol.
• Inter-individual variability was observed in plasma clearance and lung deposition, but not in Kp,u,lung or Peff.
• Drug permeability influenced intrapulmonary distribution: low-permeability drugs concentrated in ELF, high-permeability drugs in lung tissue.
• Bronchosorption plus biopsy was the most informative combination; bronchosorption alone was the best single technique.
• Optimal sampling strategies (timing and duration) depended on drug permeability.

Conclusions:

• A pulmonary population PBPK model integrating BAL, biopsy, and bronchosorption data was successfully developed for inhaled salbutamol.
• Parameter estimates for Kp,u,lung and Peff were sensitive to the sampling technique used.
• Staggered sampling strategies reduced bias, with optimal windows varying by drug permeability.
• Findings support model-informed, permeability-driven study designs for inhaled drug development.