A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions
All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current mo...
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| Format: | Article |
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Public Library of Science
2017
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| Online Access: | https://eprints.nottingham.ac.uk/51258/ |
| _version_ | 1848798453081047040 |
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| author | Cherkaoui-Rbati, Mohammed Paine, Stuart Littlewood, Peter Rauch, Cyril |
| author_facet | Cherkaoui-Rbati, Mohammed Paine, Stuart Littlewood, Peter Rauch, Cyril |
| author_sort | Cherkaoui-Rbati, Mohammed |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies. |
| first_indexed | 2025-11-14T20:20:00Z |
| format | Article |
| id | nottingham-51258 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:20:00Z |
| publishDate | 2017 |
| publisher | Public Library of Science |
| recordtype | eprints |
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| spelling | nottingham-512582020-05-04T19:06:53Z https://eprints.nottingham.ac.uk/51258/ A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions Cherkaoui-Rbati, Mohammed Paine, Stuart Littlewood, Peter Rauch, Cyril All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies. Public Library of Science 2017-09-14 Article PeerReviewed Cherkaoui-Rbati, Mohammed, Paine, Stuart, Littlewood, Peter and Rauch, Cyril (2017) A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions. PLoS ONE, 12 (9). pp. 1-28. ISSN 1932-6203 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183794 doi.org/10.1371/journal.pone.0183794 doi.org/10.1371/journal.pone.0183794 |
| spellingShingle | Cherkaoui-Rbati, Mohammed Paine, Stuart Littlewood, Peter Rauch, Cyril A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions |
| title | A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug
interactions |
| title_full | A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug
interactions |
| title_fullStr | A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug
interactions |
| title_full_unstemmed | A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug
interactions |
| title_short | A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug
interactions |
| title_sort | quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug
interactions |
| url | https://eprints.nottingham.ac.uk/51258/ https://eprints.nottingham.ac.uk/51258/ https://eprints.nottingham.ac.uk/51258/ |