Date Published: May 11, 2020
Publisher: Springer International Publishing
Author(s): Johanna Eriksson, Erik Sjögren, Hans Lennernäs, Helena Thörn.
The ex vivo isolated perfused rat lung (IPL) model has been demonstrated to be a useful tool during drug development for studying pulmonary drug absorption. This study aims to investigate the potential use of IPL data to predict rat in vivo lung absorption. Absorption parameters determined from IPL data (ex vivo input parameters) in combination with intravenously determined pharmacokinetic data were used in a biopharmaceutics model to predict experimental rat in vivo plasma concentration-time profiles and lung amount after inhalation of five different inhalation compounds. The performance of simulations using ex vivo input parameters was compared with simulations using in vitro input parameters, to determine whether and to what extent predictability could be improved by using input parameters determined from the more complex ex vivo model. Simulations using ex vivo input parameters were within twofold average difference (AAFE < 2) from experimental in vivo data for all compounds except one. Furthermore, simulations using ex vivo input parameters performed significantly better than simulations using in vitro input parameters in predicting in vivo lung absorption. It could therefore be advantageous to base predictions of drug performance on IPL data rather than on in vitro data during drug development to increase mechanistic understanding of pulmonary drug absorption and to better understand how different substance properties and formulations might affect in vivo behavior of inhalation compounds.
Pulmonary drug delivery is the preferred administration route for the treatment of lung diseases such as asthma, chronic obstructive lung disease, and cystic fibrosis (1). Optimal pulmonary drug delivery of locally acting active pharmaceutical ingredients (APIs) includes high local concentration, extended lung residence time, and low systemic concentration (2). These properties enhance the pharmacological effect and decrease the dosing frequency, which improves compliance and reduces the risk of systemically adverse effects (2). To ensure the efficient and successful development of inhalation drug products, improved knowledge about the pulmonary drug absorption, i.e., dissolution, permeability, and tissue retention of the API in the lungs, is needed (3).
Lung-specific absorption parameters obtained via the IPL model were used to simulate rat in vivo plasma concentration-time profile and lung amount for five different inhalation compounds. Simulations were within 2-fold absolute average error (AAFE) of the experimental in vivo rat data, with the exception of fluticasone propionate, indicating that drug absorption parameters obtained from the IPL model are predictive of in vivo lung absorption. Simulations using in vitro input parameters were compared with simulations using ex vivo input parameters, and those based on ex vivo parameters were significantly more accurate (as indicated by lower AAFE values) for the investigated APIs (except for salmeterol where the difference in AAFE was insignificant). These results demonstrate the advantage of the IPL method over in vitro methods for determining input parameters for predictions of in vivo plasma concentration-time profile and lung amount. In contrast to in vitro models, the IPL model resembles the in vivo dissolution better because it offers physiologically relevant volume, fluid composition, and sink/non-sink conditions. IPL also resembles in vivo permeability better because the epithelial membrane is the same as would be found in an in vivo experiment; for similar reasons, IPL resembles in vivo tissue retention better than in vitro because it offers the same volume, tissue composition, and dynamic binding processes. In addition, IPL includes the diversity and complexity of lung structure, including differences in the abovementioned parameters between the alveolar and tracheobronchial regions.
This study has further demonstrated the usefulness of data obtained with IPL by showing that absorption parameters obtained by this method yield better predictions of rat in vivo lung absorption of both solution and suspension formulations than absorption parameters determined from standard in vitro measurements. It would be advantageous to use predictions based on IPL data during drug development in order to increase mechanistic understanding of the pulmonary drug absorption processes and to better predict how changes in drug substance properties and formulation will affect the in vivo performance of inhalation compounds.