A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man

N. van de Pas

Research output: Thesisinternal PhD, WUAcademic

Abstract

An increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. However, individuals vary largely in their response to cholesterol lowering drugs and 40% of them, do not reach their cholesterol-lowering target. Development of novel therapies, for example combinations of existing drugs, can be accelerated by more mechanistic understanding of cholesterol metabolism. This understanding can be improved using computational models.

This thesis describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. For this purpose, first a PBK model for the mouse was set up, calibrated and validated, using ensemble modeling. Then the mouse model was converted to a model for humans. It describes the 21 most influential physiological reactions affecting cholesterol concentrations in 8 pools, including liver, HDL, and non-HDL. The model was parameterized using literature data and validated using clinical data for human mutations and drug interventions, taken from literature.

The model was applied to find properties that determine the individual response to drugs. The processes: hepatic cholesterol synthesis, peripheral cholesterol synthesis, and hepatic cholesterol esterification were major determinants of the non-HDL-C response to the cholesterol-lowering drug pravastatin.

We conclude that plasma cholesterol concentrations and effects of genetic polymorphisms and drugs thereupon can be predicted in silico and thatPBK modeling can provide novel mechanistic insights. 

LanguageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
Supervisors/Advisors
  • Rietjens, Ivonne, Promotor
  • Woutersen, Ruud, Promotor
  • de Graaf, A.A., Co-promotor, External person
Award date23 Dec 2011
Place of Publication[S.l.]
Publisher
Print ISBNs9789461731258
Publication statusPublished - 2011

Fingerprint

Cholesterol
Pharmaceutical Preparations
Liver
Pravastatin
Esterification
Genetic Polymorphisms
Drug Combinations
Computer Simulation
Cardiovascular Diseases
Mutation

Keywords

  • cholesterol metabolism
  • clearance
  • animal physiology
  • men

Cite this

@phdthesis{27d4d314760f49f9bff13be1dbc48543,
title = "A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man",
abstract = "An increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. However, individuals vary largely in their response to cholesterol lowering drugs and 40{\%} of them, do not reach their cholesterol-lowering target. Development of novel therapies, for example combinations of existing drugs, can be accelerated by more mechanistic understanding of cholesterol metabolism. This understanding can be improved using computational models. This thesis describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. For this purpose, first a PBK model for the mouse was set up, calibrated and validated, using ensemble modeling. Then the mouse model was converted to a model for humans. It describes the 21 most influential physiological reactions affecting cholesterol concentrations in 8 pools, including liver, HDL, and non-HDL. The model was parameterized using literature data and validated using clinical data for human mutations and drug interventions, taken from literature. The model was applied to find properties that determine the individual response to drugs. The processes: hepatic cholesterol synthesis, peripheral cholesterol synthesis, and hepatic cholesterol esterification were major determinants of the non-HDL-C response to the cholesterol-lowering drug pravastatin. We conclude that plasma cholesterol concentrations and effects of genetic polymorphisms and drugs thereupon can be predicted in silico and thatPBK modeling can provide novel mechanistic insights. ",
keywords = "cholesterolmetabolisme, klaring (plasma), dierfysiologie, mannen, cholesterol metabolism, clearance, animal physiology, men",
author = "{van de Pas}, N.",
note = "WU-thesis no. 5160",
year = "2011",
language = "English",
isbn = "9789461731258",
publisher = "S.n.",
school = "Wageningen University",

}

van de Pas, N 2011, 'A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man', Doctor of Philosophy, Wageningen University, [S.l.].

A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man. / van de Pas, N.

[S.l.] : S.n., 2011.

Research output: Thesisinternal PhD, WUAcademic

TY - THES

T1 - A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man

AU - van de Pas, N.

N1 - WU-thesis no. 5160

PY - 2011

Y1 - 2011

N2 - An increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. However, individuals vary largely in their response to cholesterol lowering drugs and 40% of them, do not reach their cholesterol-lowering target. Development of novel therapies, for example combinations of existing drugs, can be accelerated by more mechanistic understanding of cholesterol metabolism. This understanding can be improved using computational models. This thesis describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. For this purpose, first a PBK model for the mouse was set up, calibrated and validated, using ensemble modeling. Then the mouse model was converted to a model for humans. It describes the 21 most influential physiological reactions affecting cholesterol concentrations in 8 pools, including liver, HDL, and non-HDL. The model was parameterized using literature data and validated using clinical data for human mutations and drug interventions, taken from literature. The model was applied to find properties that determine the individual response to drugs. The processes: hepatic cholesterol synthesis, peripheral cholesterol synthesis, and hepatic cholesterol esterification were major determinants of the non-HDL-C response to the cholesterol-lowering drug pravastatin. We conclude that plasma cholesterol concentrations and effects of genetic polymorphisms and drugs thereupon can be predicted in silico and thatPBK modeling can provide novel mechanistic insights. 

AB - An increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. However, individuals vary largely in their response to cholesterol lowering drugs and 40% of them, do not reach their cholesterol-lowering target. Development of novel therapies, for example combinations of existing drugs, can be accelerated by more mechanistic understanding of cholesterol metabolism. This understanding can be improved using computational models. This thesis describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. For this purpose, first a PBK model for the mouse was set up, calibrated and validated, using ensemble modeling. Then the mouse model was converted to a model for humans. It describes the 21 most influential physiological reactions affecting cholesterol concentrations in 8 pools, including liver, HDL, and non-HDL. The model was parameterized using literature data and validated using clinical data for human mutations and drug interventions, taken from literature. The model was applied to find properties that determine the individual response to drugs. The processes: hepatic cholesterol synthesis, peripheral cholesterol synthesis, and hepatic cholesterol esterification were major determinants of the non-HDL-C response to the cholesterol-lowering drug pravastatin. We conclude that plasma cholesterol concentrations and effects of genetic polymorphisms and drugs thereupon can be predicted in silico and thatPBK modeling can provide novel mechanistic insights. 

KW - cholesterolmetabolisme

KW - klaring (plasma)

KW - dierfysiologie

KW - mannen

KW - cholesterol metabolism

KW - clearance

KW - animal physiology

KW - men

M3 - internal PhD, WU

SN - 9789461731258

PB - S.n.

CY - [S.l.]

ER -