In Vitro Tests for Aerosol Deposition. I: Scaling a Physical Model of the Upper Airways to Predict Drug Deposition Variation in Normal Humans

Background: In vitro-in vivo correlations (IVIVCs) are needed to relate in vitro test results for deposition to mean data from clinical trials, as well as the extremes in a population. Because drug deposition variations are related to differences in airway dimensions and inhalation profiles, this article describes the development and validation of models and methods to predict in vivo results. Methods: Three physical models of the upper airways were designed as small, medium, and large versions to represent 95% of the normal adult human population. The physical dimensions were validated by reference to anatomy literature. The models were constructed by rapid prototyping, housed in an artificial thorax, and used for in vitro testing of drug deposition from 200 mu g Budelin Novolizers using a breath simulator to mimic the inhalation profiles used in the clinic. In vitro results were compared to those reported in vivo. Results: The average'' modelwas scaled to produce small'' and large'' versions by multiplying linear dimensions by 0.748 or 1.165, respectively, based on reports of the mean and standard deviation of airway volume across a normal adult population. In vitro deposition variation under fixed test conditions was small. Testing in the model triplet however, using air flow rate versus time profiles based on the mean and the extremes reported in the clinic, produced results for total lung deposition (TLD) in vitro consistent with the complete range of drug deposition results reported in vivo. The effects of variables such as flow rate in vitro were also predictive of in vivo deposition. Conclusions: A new in vitro test method is described to predict the median and range of aerosol drug deposition seen in vivo. The method produced an IVIVC that was consistent with 1:1 predictions of total lung deposition from a marketed powder inhaler in trained normal adults.