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Development of a Physiologically Based Pharmacokinetic (PBPK) Model for the Inhalational Route

: Nowak, Norman; Winkler, Daniel Sandro; Escher, Sylvia E.; Hansen, T.; Blümlein, Katharina; Schwarz, Katharina

Journal of aerosol medicine and pulmonary drug delivery 32 (2019), No.3, pp.A38, Abstract O-111
ISSN: 1941-2711
ISSN: 1941-2703
International Society for Aerosols in Medicine (ISAM International Congress) <22, 2019, Montreux>
Fraunhofer ITEM ()

For the pre‐clinical development of new drugs and for safety assessment of chemicals PBPK‐modeling is an attractive tool. A general Physiologically‐Based Pharmacokinetic (PBPK) model for airborne substances with special focus on inhalation as portal of entry has been developed. It simulates substance transport through the lung into the systemic circulation and considers further relevant processes for removal of inhaled substances from the lung. To simulate internal doses in the human plasma and tissues, the PBPK‐model uses in‐silico and in‐vitro parameter. Permeation values under air‐liquid‐conditions are derived from human cell or tissue models using e.g. the P.R.I.T air‐liquid exposure system, or ex vivo models like the Isolated Perfused Rat Lung (IPL).For a small molecule substance with many ADME‐parameter available, an effective transfer velocity has been determined using the IPL. Comparison of temporal substance concentration profile calculated by the PBPK model to human data shows good agreement. The principal applicability of the PBPK‐model to simulate nanoparticle (NP) uptake and bio‐distribution after inhalation has been successfully shown for one NP substance. In future, it is envisaged to improve the model by a more detailed inclusion of mucociliary and macrophage‐mediated clearance and dissolution. The applicability of dissolution rates and further biological parameters determined in vitro, such as metabolization rates for lung and liver, will also be investigated.