Regression analysis of a physiologically based pharmacokinetic model (PBPK) for α₁-protease-inhibitor (API) disposition after IV-infusion

Objective: To predict lung interstitial (INT) concentrations of API ([API]) after IV infusion using a PBPK model with parameters based on published lung epithelial lining fluid (ELF) and venous plasma concentrations (VP). A tissue PBPK model with flow and membrane limited compartments was employed using published human VP and lung ELF [API]s. Selected model parameters were estimated using ELF and VP [API]s simultaneously. Estimated blood volume =0.05% bodyweight (95%-CI: 0.04-0.06). Plasma API- and ELF-fractional turnover rates =0.26/d (0.22-0.30) and 0.35/d (0.18-0.67), respectively. Permeability-area product across the alveolar epithelial membrane =0.006 1/d (0.004-0.009). Conclusions: 1. Simultaneous analysis of [API] in 2 tissues provided estimates of critical model-parameters. 2. PBPK was able to predict [API]-time profiles in INT.