IVIVC using in silico and PBPK methods for inhaled drug product development
Viera Lukacova1, Walter Woltosz1, Beverley Patterson2
1Simulations Plus, Inc., 42505 10th Street West, Lancaster, CA 93534, USA
2formerly Actavis, UK
Background: The physiologically based model of the lung included in GastroPlus™ was used to simulate the absorption, distribution, and pharmacokinetics of two APIs from an inhaled combination product. The goal of the study was to evaluate the possibility of developing an in vitro-in vivo correlation (IVIVC) to aid in the development of generic inhaled drug products.
Methods: Physiologically based pharmacokinetic (PBPK) models for both APIs were developed using the PBPKPlus™ and PCAT™ modules in GastroPlus based on literature data after intravenous (iv), oral (po), and inhaled administration. The baseline models were refined by fitting total lung deposition and dissolution rate against Cp-time profiles for APIs from inhaled administration of the reference product. The in vitro and in vivo dissolution rates from the reference product were used to create an IVIVC, which was used to predict the systemic exposure for test products with the same combination of APIs. The effect of dissolution rate and lung deposition on the predicted exposure was explored.
Results: The PCAT/PBPK models accurately described the systemic exposure of both APIs from the reference product. The dissolution-based IVIVC underpredicted the systemic exposure of APIs from test products. This misprediction appeared to be caused by variability in the lung deposition between formulations rather than by an inaccurate dissolution rate.
Conclusion: This study showed the potential of using an IVIVC to evaluate the in vivo dissolution for inhaled products. However, a sensitive method for predicting the differences in lung deposition is required for accurate prediction of overall performance of formulations.