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Interspecies and in vitro‐in vivo scaling for quantitative modeling of whole‐body drug pharmacokinetics in patients : application to the anticancer drug oxaliplatin
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Catozzi, Simona, Hill, Roger, Li, Xiao‐Mei, Dulong, Sandrine, Collard, Elodie and Ballesta, Annabelle (2023) Interspecies and in vitro‐in vivo scaling for quantitative modeling of whole‐body drug pharmacokinetics in patients : application to the anticancer drug oxaliplatin. CPT: pharmacometrics & systems pharmacology, 12 (2). pp. 221-235. doi:10.1002/psp4.12895 ISSN 2163-8306.
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Official URL: http://doi.org/10.1002/psp4.12895
Abstract
Quantitative systems pharmacology holds the promises of integrating results from laboratory animals or in vitro human systems into the design of human pharmacokinetic/pharmacodynamic (PK/PD) models allowing for precision and personalized medicine. However, reliable and general in vitro-to-in vivo extrapolation and interspecies scaling methods are still lacking. Here, we developed a translational strategy for the anticancer drug oxaliplatin. Using ex vivo PK data in the whole blood of the mouse, rat, and human, a model representing the amount of platinum (Pt) in the plasma and in the red blood cells was designed and could faithfully fit each dataset independently. A “purely physiologically-based (PB)” scaling approach solely based on preclinical data failed to reproduce human observations, which were then included in the calibration. Investigating approaches in which one parameter was set as species-specific, whereas the others were computed by PB scaling laws, we concluded that allowing the Pt binding rate to plasma proteins to be species-specific permitted to closely fit all data, and guaranteed parameter identifiability. Such a strategy presenting the drawback of including all clinical datasets, we further identified a minimal subset of human data ensuring accurate model calibration. Next, a “whole body” model of oxaliplatin human PK was inferred from the ex vivo study. Its three remaining parameters were estimated, using one third of the available patient data. Remarkably, the model achieved a good fit to the training dataset and successfully reproduced the unseen observations. Such validation endorsed the legitimacy of our scaling methodology calling for its testing with other drugs.
Item Type: | Journal Article | ||||||||||||||||||
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Subjects: | Q Science > QH Natural history R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology T Technology > TA Engineering (General). Civil engineering (General) |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Mathematics Faculty of Science, Engineering and Medicine > Research Centres > Molecular Organisation and Assembly in Cells (MOAC) |
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Library of Congress Subject Headings (LCSH): | Oxaliplatin , Pharmacology, Systems engineering, Pharmacokinetics, Pharmacokinetics -- Mathematical models, Drugs -- Design, Biological models | ||||||||||||||||||
Journal or Publication Title: | CPT: pharmacometrics & systems pharmacology | ||||||||||||||||||
Publisher: | Wiley-Blackwell Publishing Ltd. | ||||||||||||||||||
ISSN: | 2163-8306 | ||||||||||||||||||
Official Date: | February 2023 | ||||||||||||||||||
Dates: |
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Volume: | 12 | ||||||||||||||||||
Number: | 2 | ||||||||||||||||||
Page Range: | pp. 221-235 | ||||||||||||||||||
DOI: | 10.1002/psp4.12895 | ||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||
Copyright Holders: | © 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | ||||||||||||||||||
Date of first compliant deposit: | 7 February 2023 | ||||||||||||||||||
Date of first compliant Open Access: | 7 February 2023 | ||||||||||||||||||
RIOXX Funder/Project Grant: |
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