title: In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery.
abstract: Despite the interest in systemic delivery of therapeutic molecules including macromolecular proteins and peptides via the lung, the accurate assessment of their pulmonary biopharmaceutics is a challenging experimental task. This article reviews in vivo, in vitro and ex vivo models currently available for studying lung absorption and disposition for inhaled therapeutic molecules. The general methodologies are discussed with recent advances, current challenges and perspectives, especially in the context of their use in systemic pulmonary delivery research. In vivo approaches in small rodents continue to be the mainstay of assessment by virtue of the acquisition of direct pharmacokinetic data, more meaningful when attention is given to reproducible dosing and control of lung-regional distribution through use of more sophisticated lung-dosing methods, such as forced instillation, microspray, nebulization and aerosol puff. A variety of in vitro lung epithelial cell lines models and primary cultured alveolar epithelial (AE) cells when grown to monolayer status offer new opportunity to clarify the more detailed kinetics and mechanisms of transepithelial drug transport. While continuous cell lines, Calu-3 and 16HBE14o-, show potential, primary cultured AE cell models from rat and human origins may be of greater use, by virtue of their universally tight intercellular junctions that discriminate the transport kinetics of different therapeutic entities. Nevertheless, the relevance of using these reconstructed barriers to represent complex disposition of intact lung may still be debatable. Meanwhile, the intermediate ex vivo model of the isolated perfused lung (IPL) appears to resolve deficiencies of these in vivo and in vitro models. While controlling lung-regional distributions, the preparation alongside a novel kinetic modeling analysis enables separate determinations of kinetic descriptors for lung absorption and non-absorptive clearances, i.e., mucociliary clearance, phagocytosis and/or metabolism. This ex vivo model has been shown to be kinetically predictive of in vivo, with respect to macromolecular disposition, despite limitations concerning short viable periods of 2-3 h and likely absence of tracheobronchial circulation. Given the advantages and disadvantages of each model, scientists must make appropriate selection and timely exploitation of the best model at each stage of the research and development program, affording efficient progress toward clinical trials for future inhaled therapeutic entities for systemic delivery.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 North 12th Street, P.O. Box 980533, Richmond, VA 23298-0533, USA. msakagam@vcu.edu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
mesh_terms: D000042:Absorption; D000280:Administration, Inhalation; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D014018:Tissue Distribution
chemical_list: D004364:Pharmaceutical Preparations