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Predicting individual responses to pravastatin using a physiologically based kinetic model for plasma cholesterol concentrations

  • Niek C. A. van de Pas
  • Johan A. C. Rullmann
  • Ruud A. Woutersen
  • Ben van Ommen
  • Ivonne M. C. M. Rietjens
  • Albert A. de Graaf
Original Paper

Abstract

We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body cholesterol pools including plasma HDL and non-HDL cholesterol. A pravastatin pharmacokinetic model was constructed and the simulated hepatic pravastatin concentration was used to modulate the reaction rate constant of hepatic free cholesterol synthesis in the PBK model. The integrated model was then used to predict plasma cholesterol concentrations as a function of pravastatin dose. Predicted versus observed values at 40 mg/d pravastatin were 15 versus 22 % reduction of total plasma cholesterol, and 10 versus 5.6 % increase of HDL cholesterol. A population of 7,609 virtual subjects was generated using a Monte Carlo approach, and the response to a 40 mg/d pravastatin dose was simulated for each subject. Linear regression analysis of the pravastatin response in this virtual population showed that hepatic and peripheral cholesterol synthesis had the largest regression coefficients for the non-HDL-C response. However, the modeling also showed that these processes alone did not suffice to predict non-HDL-C response to pravastatin, contradicting the hypothesis that people with high cholesterol synthesis rates are good statin responders. In conclusion, we have developed a PBK model that is able to accurately describe the effect of pravastatin treatment on plasma cholesterol concentrations and can be used to provide insight in the mechanisms behind individual variation in statin response.

Keywords

Personalized medicine Virtual subjects LDL Cholesterol Statin response PBK modeling 

Abbreviations

C

Cholesterol

CE

Cholesterol ester

FC

Free cholesterol

HDL

High density lipoprotein

HMG-CoA reductase

3-hydroxy-3-methyl-glutaryl-CoA reductase

LDL

Low density lipoprotein

LDLR

LDL receptor

PBK

Physiologically based kinetic

TC

Total plasma cholesterol

UDCA

Ursodeoxycholic acid

VLDL

Very low density lipoprotein

Notes

Acknowledgments

We thank Sieto Bosgra for assistance with the pravastatin PBPK model.

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Niek C. A. van de Pas
    • 1
    • 2
    • 3
  • Johan A. C. Rullmann
    • 1
  • Ruud A. Woutersen
    • 1
    • 2
    • 3
  • Ben van Ommen
    • 1
  • Ivonne M. C. M. Rietjens
    • 2
    • 3
  • Albert A. de Graaf
    • 1
  1. 1.The Netherlands Organization for Applied Scientific Research (TNO)ZeistThe Netherlands
  2. 2.Division of ToxicologyWageningen UniversityWageningenThe Netherlands
  3. 3.TNO/WUR Centre for Innovative ToxicologyWageningenThe Netherlands

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