Insights into humidity-induced changes on the in-vitro pulmonary deposition and the predicted plasma levels of budesonide from commercial DPIs: a pharmacokinetic model assisted risk assessment approach
S Radivojev1,2, J T Pinto1, E Fröhlich1,2 & A Paudel1,3
1Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, Graz, 8010, Austria
2Center for Medical Research, Medical University of Graz, Stiftingtalstraße 24, Graz, 8010, Austria
3Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, Graz, 8010, Austria
In-silico studies are recognized as a strategy to facilitate the development of new pharmaceutical products and/or assess post-approval changes to the manufacturing process or formulation. In-silico predictions can be utilized to understand the interplay between the physicochemical characteristics of the formulation and drug pharmacokinetics (PK). The aim of this study was to explore the impact of different storage conditions on the in-vitro deposition profiles of two commercially available dry powder inhaler (DPI) formulations of budesonide, namely Easyhaler® and Novolizer®, predicting the potential changes on in-vivo PK parameters. Sensitivity of DPI formulations to humidity is increasingly being reported in the literature. However, their potential relevance on in-vivo performance is not yet clear. Utilization of distinct in-vitro deposition profiles found over time after storage under 60% and >90% relative humidity (RH) in the in-silico PK model resulted into the predicted PK parameters demonstrating different extents of impact depending on formulation characteristics. In general, a slight decrease in the in-vitro deposited fraction of drug in the peripheral lung (over time) was observed for Novolizer®. This yielded a subtle change in the predicted PK parameters for the samples stored at different time points, yet, no notable difference could be found between the two storage conditions. For Easyhaler®, a time-dependent decrease in the trend in delivered dose of the drug was identified, especially when inhalers were stored at >90% RH. This directly impacted budesonide plasma concentration profiles predicted in-silico. These first set of data demonstrated that during product development, the risk of the change in the in-vivo fate of DPI induced mishandling, namely storage at extreme RH can be accessed by combining in-vitro and in-silico approaches.