Montanha, Maiara Camotti, Howarth, Alice 
ORCID: 0000-0003-2288-1745, Mohamed, Doaa Ahmed, Loier, Estelle, Main, Lauren, Rosslein, Matthias, Delmaar, Christiaan, Prina-Mello, Adriele and Siccardi, Marco ORCID: 0000-0002-3539-7867
(2022)
A physiologically based pharmacokinetic model to predict pegylated liposomal doxorubicin disposition in rats and human.
DRUG DELIVERY AND TRANSLATIONAL RESEARCH, 12 (9).
pp. 2178-2186.
Abstract
The use of nanoparticles (NPs) can support an enhancement of drug distribution, resulting in increased drug penetration into key tissues. Experimental in vitro data can be integrated into computational approaches to simulate NP absorption, distribution, metabolism and elimination (ADME) processes and provide quantitative pharmacokinetic predictions. The aim of this study is to develop a novel mechanistic and physiologically based pharmacokinetic (m-PBPK) model to predict the biodistribution of NPs focusing on Doxil. The main processes underpinning NPs ADME were represented considering molecular and cellular mechanisms such as stability in biological fluids, passive permeability and uptake activity by macrophages. A whole-body m-PBPK rat and human models were designed in Simbiology v. 9.6.0 (MATLAB R2019a). The m-PBPK models were successfully qualified across doxorubicin and Doxil<sup>®</sup> in both rat and human since all PK parameters AUC<sub>0-inf</sub>, C<sub>max</sub>, t<sub>1/2</sub>, Vd and Cl were within twofold, with an AUC<sub>0-inf</sub> absolute average-fold error (AAFE) value of 1.23 and 1.16 and 1.76 and 1.05 for Doxorubicin and Doxil<sup>®</sup> in rat and human, respectively. The time to maximum concentration in tissues for doxorubicin in both rat and human models was before 30 min of administration, while for Doxil<sup>®</sup>, the t<sub>max</sub> was after 24 h of administration. The organs that accumulate most NP are the spleen, liver and lungs, in both models. The m-PBPK represents a predictive platform for the integration of in vitro and formulation parameters in a physiological context to quantitatively predict the NP biodistribution. Schematic diagram of the whole-body m-PBPK models developed for Doxil<sup>®</sup> in rat and human physiology.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Biodistribution, Doxil, In silico modelling, Nanoparticles, Physiologically based pharmacokinetic (PBPK) |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 28 Mar 2023 08:10 |
| Last Modified: | 24 Jan 2024 18:56 |
| DOI: | 10.1007/s13346-022-01175-w |
| Open Access URL: | https://assets.researchsquare.com/files/rs-1417093... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3169272 |
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