Interspecies evaluation of a physiologically based pharmacokinetic model to predict the biodistribution dynamics of dendritic nanoparticles.

Autor: Vasalou C; Oncology R&D, AstraZeneca, Boston, Massachusetts, United States of America., Harding J; Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Jones RDO; Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Hariparsad N; Oncology R&D, AstraZeneca, Boston, Massachusetts, United States of America., McGinnity DF; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 May 17; Vol. 18 (5), pp. e0285798. Date of Electronic Publication: 2023 May 17 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0285798
Abstrakt: The exposure of a dendritic nanoparticle and its conjugated active pharmaceutical ingredient (API) was determined in mouse, rat and dog, with the aim of investigating interspecies differences facilitating clinical translation. Plasma area under the curves (AUCs) were found to be dose proportional across species, while dose normalized concentration time course profiles in plasma, liver and spleen were superimposable in mouse, rat and dog. A physiologically based pharmacokinetic (PBPK) model, previously developed for mouse, was evaluated as a suitable framework to prospectively capture concentration dynamics in rat and dog. The PBPK model, parameterized either by considering species-specific physiology or using alternate scaling methods such as allometry, was shown to capture exposure profiles across species. A sensitivity analysis highlighted API systemic clearance as a key parameter influencing released API levels. The PBPK model was utilized to simulate human exposure profiles, which overlaid dose-normalized data from mouse, rat and dog. The consistency in measured interspecies exposures as well as the capability of the PBPK model to simulate observed dynamics support its use as a powerful translational tool.
Competing Interests: “ All authors were employees and/or shareholders of Astrazeneca at the time of study completion. This does not alter our adherence to PLOS ONE policies on sharing data and
(Copyright: © 2023 Vasalou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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