Integrating in vitro aerosol characterization and cross-species PBPK modeling to predict human lung exposure of inhaled therapeutic proteins

Inhalation therapy provides a rapid onset and avoids first-pass metabolism, making it a key non-invasive delivery strategy for therapeutic proteins. However, predicting pulmonary exposure is challenging due to aerosol properties and lung anatomy. This study is the first to construct an integrated in vitro aerosol characterization and cross-species extrapolation pulmonary physiologically-based pharmacokinetic (PBPK) model for inhaled therapeutic proteins. Using recombinant human interferon-α1b (rhIFN-α1b) as a model drug, aerosol aerodynamic properties and delivery performance were evaluated at different concentrations (15–60 μg/mL) and inhalation devices (mouthpiece vs. facemask). The multiple path particle dosimetry (MPPD) model was used to predict particle deposition in the lungs. Further, a pulmonary PBPK model for rhIFN-α1b in mice and healthy adults was developed and validated through pharmacokinetic studies. Results showed that delivery efficiency decreased with concentration, and the mouthpiece outperformed the mask. MPPD simulations indicated that the mouthpiece reduced oropharyngeal retention and enhanced alveolar deposition. Larger particle sizes led to reduced alveolar deposition. The PBPK model accurately predicted rhIFN-α1b exposure in the lungs and serum of healthy adults, with 85% of C max and AUC 0-inf values falling within a 0.5–2.0–fold error range. This study provides a quantitative platform for clinical translation and dosing regimen evaluation of inhaled therapeutic proteins.