Lung-Sim: a Physiologically Based Biopharmaceutical Prediction tool  

Ulrika Tehler¹, Rebecca Fransson¹, Helena Thörn², Frans Franek² & Jan Westergren³

¹AstraZeneca R&D, Pharmaceutical Sciences, Pepparedsleden 1, Mölndal, 43183, Sweden

²AstraZeneca R&D, Pharmaceutical Technology & Development Inhalation, Pepparedsleden 1, Mölndal, 43183, Sweden

³Wendelbergs beräkningskemi AB, Kyrkvägen 7B, Mölnlycke, 43535, Sweden

Summary

A physiologically based biopharmaceutical prediction tool called Lung-Sim has been developed and described. The Lung-Sim model has been evaluated both pre-clinically and clinically for a nonsteroidal selective glucocorticoid receptor modulator administered via the inhaled route. The model was built to mechanistically address the preclinical-clinical translation challenges and to provide predictive confidence when bridging between different devices/formulations during development. The influence of material properties, different formulations, and administration techniques on lung absorption was predicted and compared to observed experimental data for both rat and healthy human volunteers. The predictions were in excellent agreement with the observed data for all the investigations attempted. Therefore, the Lung-Sim modelling platform seems to adequately describe the major events taking place in the lung after an inhaled dose, i.e. deposition, mucociliary clearance, dissolution, permeation in to the lung tissue and systemic distribution. The successful prediction of clinical PK data for two different formulations of AZD5423, a nebulised suspension and a dry powder formulation administrated with two different devices, suggest that we have built a sophisticated human PBBP model for compound with dissolution rate controlled lung retention. These results suggest that in silico based mechanistic models can be used as research tools to predict and understand systemic plasma exposures following inhaled administration of drug candidates, formulations and inhaled devices that are being explored during the pharmaceutical drug development process.