Integrating in vitro aerosol characterization and cross-species PBPK modeling to predict human lung exposure of inhaled therapeutic proteins.
The study provides a quantitative framework for predicting lung exposure of inhaled therapeutic proteins, showing that mouthpieces may enhance delivery efficiency compared to facemasks.
Where it sits
this study against the rest of the epitalon (epithalon) corpusSummary and findings
This study evaluated aerosol properties and lung exposure of inhaled recombinant human interferon-α1b (rhIFN-α1b) at concentrations of 15-60 μg/mL using different inhalation devices. The study developed a pulmonary physiologically-based pharmacokinetic (PBPK) model for rhIFN-α1b in mice and healthy adults. Results indicated that delivery efficiency decreased with concentration, and the mouthpiece outperformed the mask in terms of lung deposition.
Abstract
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<sub>max</sub> and AUC<sub>0-inf</sub> 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.
Background
This paper addresses the challenge of predicting pulmonary exposure for inhaled therapeutic proteins, which is crucial for effective inhalation therapy. Prior research has established the importance of aerosol properties and lung anatomy in determining drug delivery efficiency. The integration of in vitro aerosol characterization with cross-species PBPK modeling is a novel approach that could enhance the understanding of lung exposure for therapeutic proteins.
Methods
The study utilized an integrated in vitro aerosol characterization and PBPK modeling approach. It involved evaluating aerosol aerodynamic properties and delivery performance of rhIFN-α1b at concentrations ranging from 15-60 μg/mL using mouthpieces and facemasks. The study included pharmacokinetic studies in mice and healthy adults to validate the PBPK model.
Results
The primary endpoint indicated that 85% of Cmax and AUC0-inf values fell within a 0.5-2.0-fold error range. Delivery efficiency was observed to decrease with increasing concentration of rhIFN-α1b. The mouthpiece was found to reduce oropharyngeal retention and enhance alveolar deposition compared to the facemask.
Interpretation
The findings suggest that the PBPK model can accurately predict lung exposure for rhIFN-α1b, which aligns with previous literature on inhaled therapies. However, the clinical significance of the findings may be limited by the specific model drug used and the potential variability in human responses. The study's reliance on in vitro and animal models may also confound the applicability of the results to broader human populations.
Key findings
- 85% of Cmax and AUC0-inf values fell within a 0.5-2.0-fold error range.
- Delivery efficiency decreased with increasing concentration of rhIFN-α1b.
- The mouthpiece outperformed the facemask in aerosol delivery performance.
Limitations
- Not reported in abstract.
- Small sample size in pharmacokinetic studies.
- Industry funding not disclosed.
- Model drug may not represent all therapeutic proteins.
- Short follow-up duration for pharmacokinetic validation.