Mechanistic Modelling of Inhaled Protein Aggregation in the Lung by Integrating in vivo Pharmacokinetic and in vitro Dynamic Light Scattering Data

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Examensarbete för masterexamen
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2021
Författare
Alhede, Jakob
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Protein aggregation is a broad term encompassing interactions causing protein self-associations. It has long been acknowledged protein aggregation triggers immunogenic responses. However, the clinical significance of protein aggregation is poorly understood due to the notoriously difficult task to quantify, let alone observe aggregation in vivo. This project presents a framework to predict pulmonary aggregation of inhaled biologics. Albumin from human serum was used as a model protein to develop the principles and methodology. Aggregation of albumin was characterized in vitro by dynamic light scattering, and aggregate kinetics were mathematically described by the Finke-Watzky model. The parameterized Finke-Watzky model was combined with an inhalation physiologically based pharmacokinetic model, and aggregation was simulated in the epithelial lining fluid of the central and peripheral lung. The established model proved to be very versatile, simulating repeated dosing, the influence of alveolar macrophage clearance, aggregate accumulation, and aggregation dose-dependency with great efficiency.
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Inhaled biologics, Protein aggregation, Physiologically based pharma-cokinetic modelling, Pulmonary aggregate predictions
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