In-Silico Lung Modeling Platform for Inhaled Drug Delivery in Beagle Dogs
Antonio Cabal1, Guido H. Jajamovich1, & Javad Heydari2
1Merck & Co., Inc., Kenilworth, NJ USA
2Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180 USA
Modeling and simulation can help provide otherwise unavailable information on of the local drug concentration in target tissues of the lung following canine inhaled drug delivery. The model described in this work is a multiscale mechanism-based integrated computational platform developed to provide mechanistic insights into key complex species-specific physiological-based processes associated with pulmonary drug delivery in dogs: deposition, mucociliary clearance, dissolution, absorption, transport, distribution, partition, and action. The dog version of the lung platform was developed in addition to rat and human lung platforms to account for the differences in airway morphology and drug distribution throughout the canine body. All these components facilitate a prediction of regional distribution of drug within the lungs.
Dogs are frequently used in inhalation toxicology studies; however only very limited data are available related to experimental particle matter deposition in dogs following inhaled drug delivery. Published data from the 1970s and 80s were used to qualify the deposition module of our dog lung platform (DLP) model. A comparison between oral (oropharyngeal) and nasal (breathing mask) delivery is presented in this work. The results quantify the effect of dog breathing patterns (frequency and tidal volume) in the different regions of the dog respiratory tract for these two delivery methods. The translational pharmacokinetic benefits of the lung platform are illustrated using budesonide, where the physicochemical properties and the drug delivery details constitute the main input to the model. Clearance was the only parameter adjusted using weight based allometric scaling to translate from preclinical species to humans.