Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach
Background and Objective: Statins are one of the most prescribed drugs to treat atherosclerosis. They inhibit the hepatic HMG-CoA reductase, causing a reduction of circulating cholesterol and LDL levels. Statins have had undeniable success; however, the benefits of statin therapy crystallize only if...
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doaj-7b18401fefde477aa0f1a5b79784fa512020-11-25T00:05:45ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-09-01810.3389/fphar.2017.00635258354Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale ApproachCesar Pichardo-Almarza0Cesar Pichardo-Almarza1Vanessa Diaz-Zuccarini2Vanessa Diaz-Zuccarini3Multiscale Cardiovascular Engineering Group (MUSE), Department of Mechanical Engineering, University College LondonLondon, United KingdomInstitute of Healthcare Engineering, University College LondonLondon, United KingdomMultiscale Cardiovascular Engineering Group (MUSE), Department of Mechanical Engineering, University College LondonLondon, United KingdomInstitute of Healthcare Engineering, University College LondonLondon, United KingdomBackground and Objective: Statins are one of the most prescribed drugs to treat atherosclerosis. They inhibit the hepatic HMG-CoA reductase, causing a reduction of circulating cholesterol and LDL levels. Statins have had undeniable success; however, the benefits of statin therapy crystallize only if patients adhere to the prescribed treatment, which is far away from reality since adherence decreases with time with around half of patients discontinue statin therapy within the first year. The objective of this work is to; firstly, demonstrate a formal in-silico methodology based on a hybrid, multiscale mathematical model used to study the effect of statin treatment on atherosclerosis under different patient scenarios, including cases where the influence of medication adherence is examined and secondly, to propose a flexible simulation framework that allows extensions or simplifications, allowing the possibility to design other complex simulation strategies, both interesting features for software development.Methods: Different mathematical modeling paradigms are used to present the relevant dynamic behavior observed in biological/physiological data and clinical trials. A combination of continuous and discrete event models are coupled to simulate the pharmacokinetics (PK) of statins, their pharmacodynamic (PD) effect on lipoproteins levels (e.g., LDL) and relevant inflammatory pathways whilst simultaneously studying the dynamic effect of flow-related variables on atherosclerosis progression.Results: Different scenarios were tested showing the impact of: (1) patient variability: a virtual population shows differences in plaque growth for different individuals could be as high as 100%; (2) statin effect on atherosclerosis: it is shown how a patient with a 1-year statin treatment will reduce his plaque growth by 2–3% in a 2-year period; (3) medical adherence: we show that a patient missing 10% of the total number of doses could increase the plaque growth by ~1% (after 2 years) compared to the same “regular” patient under a 1-year treatment with statins.Conclusions: The results in this paper describe the effect of pharmacological intervention combined with biological/physiological or behavioral factors in atherosclerosis progression and treatment in specific patients. It also provides an exemplar of basic research that can be practically developed into an application software.http://journal.frontiersin.org/article/10.3389/fphar.2017.00635/fullatherosclerosisstatinsmultiscale modelinghybrid modelpatient adherencepharmacokinetics/pharmacodynamics (PKPD) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cesar Pichardo-Almarza Cesar Pichardo-Almarza Vanessa Diaz-Zuccarini Vanessa Diaz-Zuccarini |
spellingShingle |
Cesar Pichardo-Almarza Cesar Pichardo-Almarza Vanessa Diaz-Zuccarini Vanessa Diaz-Zuccarini Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach Frontiers in Pharmacology atherosclerosis statins multiscale modeling hybrid model patient adherence pharmacokinetics/pharmacodynamics (PKPD) |
author_facet |
Cesar Pichardo-Almarza Cesar Pichardo-Almarza Vanessa Diaz-Zuccarini Vanessa Diaz-Zuccarini |
author_sort |
Cesar Pichardo-Almarza |
title |
Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach |
title_short |
Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach |
title_full |
Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach |
title_fullStr |
Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach |
title_full_unstemmed |
Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach |
title_sort |
understanding the effect of statins and patient adherence in atherosclerosis via a quantitative systems pharmacology model using a novel, hybrid, and multi-scale approach |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2017-09-01 |
description |
Background and Objective: Statins are one of the most prescribed drugs to treat atherosclerosis. They inhibit the hepatic HMG-CoA reductase, causing a reduction of circulating cholesterol and LDL levels. Statins have had undeniable success; however, the benefits of statin therapy crystallize only if patients adhere to the prescribed treatment, which is far away from reality since adherence decreases with time with around half of patients discontinue statin therapy within the first year. The objective of this work is to; firstly, demonstrate a formal in-silico methodology based on a hybrid, multiscale mathematical model used to study the effect of statin treatment on atherosclerosis under different patient scenarios, including cases where the influence of medication adherence is examined and secondly, to propose a flexible simulation framework that allows extensions or simplifications, allowing the possibility to design other complex simulation strategies, both interesting features for software development.Methods: Different mathematical modeling paradigms are used to present the relevant dynamic behavior observed in biological/physiological data and clinical trials. A combination of continuous and discrete event models are coupled to simulate the pharmacokinetics (PK) of statins, their pharmacodynamic (PD) effect on lipoproteins levels (e.g., LDL) and relevant inflammatory pathways whilst simultaneously studying the dynamic effect of flow-related variables on atherosclerosis progression.Results: Different scenarios were tested showing the impact of: (1) patient variability: a virtual population shows differences in plaque growth for different individuals could be as high as 100%; (2) statin effect on atherosclerosis: it is shown how a patient with a 1-year statin treatment will reduce his plaque growth by 2–3% in a 2-year period; (3) medical adherence: we show that a patient missing 10% of the total number of doses could increase the plaque growth by ~1% (after 2 years) compared to the same “regular” patient under a 1-year treatment with statins.Conclusions: The results in this paper describe the effect of pharmacological intervention combined with biological/physiological or behavioral factors in atherosclerosis progression and treatment in specific patients. It also provides an exemplar of basic research that can be practically developed into an application software. |
topic |
atherosclerosis statins multiscale modeling hybrid model patient adherence pharmacokinetics/pharmacodynamics (PKPD) |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2017.00635/full |
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