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Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics
Karolinska Institute, Sweden .
MathCore Engn AB, Linkoping, Sweden .
MathCore Engn AB, Linkoping, Sweden .
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
2012 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 47, no 4, 759-767 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To build a semi-physiologically based pharmacokinetic model describing the uptake, metabolism and efflux of paclitaxel and its metabolites and investigate the effect of hypothetical genetic polymorphisms causing reduced uptake, metabolism or efflux in the pathway by model simulation and sensitivity analysis.less thanbrgreater thanless thanbrgreater thanMethods: A previously described intracellular pharmacokinetic model was used as a starting point for model development. Kinetics for metabolism, transport, binding and systemic and output compartments were added to mimic a physiological model with hepatic elimination. Model parameters were calibrated using constraints postulated as ratios of concentrations and amounts of metabolites and drug in the systemic plasma and output compartments. The sensitivity in kinetic parameters was tested using dynamic sensitivity analysis.less thanbrgreater thanless thanbrgreater thanResults: Predicted plasma concentrations of drug and metabolites were in the range of what has been observed in clinical studies. Given the final model, plasma concentrations of paclitaxel seems to be relatively little affected by changes in metabolism or transport, while its main metabolite may be largely affected even by small changes. If metabolites prove to be clinically relevant, genetic polymorphisms may play an important role for individualizing paclitaxel treatment.

Place, publisher, year, edition, pages
Elsevier , 2012. Vol. 47, no 4, 759-767 p.
Keyword [en]
Paclitaxel metabolism, Mathematical modeling, Pharmacokinetics, Sensitivity analysis, CYP2C8, CYP3A4
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-86649DOI: 10.1016/j.ejps.2012.08.002ISI: 000311464900015OAI: oai:DiVA.org:liu-86649DiVA: diva2:580095
Note

Funding Agencies|Swedish Knowledge Foundation through the Industrial PhD programme in Medical Bioinformatics at the Strategy and Development Office (SDO) at Karolinska Institutet||Swedish Cancer Society||Swedish Research Council||

Available from: 2012-12-20 Created: 2012-12-20 Last updated: 2017-12-06

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Green, Henrik

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