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Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin
Typically, pharmacokinetic–pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concent...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120018/ https://www.ncbi.nlm.nih.gov/pubmed/25006781 http://dx.doi.org/10.1038/psp.2014.24 |
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author | Rose, R H Neuhoff, S Abduljalil, K Chetty, M Rostami-Hodjegan, A Jamei, M |
author_facet | Rose, R H Neuhoff, S Abduljalil, K Chetty, M Rostami-Hodjegan, A Jamei, M |
author_sort | Rose, R H |
collection | PubMed |
description | Typically, pharmacokinetic–pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake by the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter on the pharmacological response. The area under the plasma concentration–time curve (AUC(0–∞)) was increased by 63 and 111% for the c.521TC and c.521CC genotypes vs. the c.521TT genotype, while the PD response remained relatively unchanged (3.1 and 5.8% reduction). Using local concentration at the effect site to drive the PD response enabled us to explain the observed disconnect between the effect of the OATP1B1 c521T>C polymorphism on rosuvastatin plasma concentration and the cholesterol synthesis response. |
format | Online Article Text |
id | pubmed-4120018 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-41200182014-08-15 Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin Rose, R H Neuhoff, S Abduljalil, K Chetty, M Rostami-Hodjegan, A Jamei, M CPT Pharmacometrics Syst Pharmacol Original Article Typically, pharmacokinetic–pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake by the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter on the pharmacological response. The area under the plasma concentration–time curve (AUC(0–∞)) was increased by 63 and 111% for the c.521TC and c.521CC genotypes vs. the c.521TT genotype, while the PD response remained relatively unchanged (3.1 and 5.8% reduction). Using local concentration at the effect site to drive the PD response enabled us to explain the observed disconnect between the effect of the OATP1B1 c521T>C polymorphism on rosuvastatin plasma concentration and the cholesterol synthesis response. Nature Publishing Group 2014-07 2014-07-09 /pmc/articles/PMC4120018/ /pubmed/25006781 http://dx.doi.org/10.1038/psp.2014.24 Text en Copyright © 2014 American Society for Clinical Pharmacology and Therapeutics http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Rose, R H Neuhoff, S Abduljalil, K Chetty, M Rostami-Hodjegan, A Jamei, M Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin |
title | Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin |
title_full | Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin |
title_fullStr | Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin |
title_full_unstemmed | Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin |
title_short | Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin |
title_sort | application of a physiologically based pharmacokinetic model to predict oatp1b1-related variability in pharmacodynamics of rosuvastatin |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120018/ https://www.ncbi.nlm.nih.gov/pubmed/25006781 http://dx.doi.org/10.1038/psp.2014.24 |
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