Pharmaceutical Research

, Volume 32, Issue 6, pp 1864–1883 | Cite as

Development and Application of a Mechanistic Pharmacokinetic Model for Simvastatin and its Active Metabolite Simvastatin Acid Using an Integrated Population PBPK Approach

  • Nikolaos Tsamandouras
  • Gemma Dickinson
  • Yingying Guo
  • Stephen Hall
  • Amin Rostami-Hodjegan
  • Aleksandra Galetin
  • Leon Aarons
Research Paper



To develop a population physiologically-based pharmacokinetic (PBPK) model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that allows extrapolation and prediction of their concentration profiles in liver (efficacy) and muscle (toxicity).


SV/SVA plasma concentrations (34 healthy volunteers) were simultaneously analysed with NONMEM 7.2. The implemented mechanistic model has a complex compartmental structure allowing inter-conversion between SV and SVA in different tissues. Prior information for model parameters was extracted from different sources to construct appropriate prior distributions that support parameter estimation. The model was employed to provide predictions regarding the effects of a range of clinically important conditions on the SV and SVA disposition.


The developed model offered a very good description of the available plasma SV/SVA data. It was also able to describe previously observed effects of an OATP1B1 polymorphism (c.521 T > C) and a range of drug-drug interactions (CYP inhibition) on SV/SVA plasma concentrations. The predicted SV/SVA liver and muscle tissue concentrations were in agreement with the clinically observed efficacy and toxicity outcomes of the investigated conditions.


A mechanistically sound SV/SVA population model with clinical applications (e.g., assessment of drug-drug interaction and myopathy risk) was developed, illustrating the advantages of an integrated population PBPK approach.


“drug-drug interactions” “OATP1B1” “PBPK” “population model” “simvastatin” 



Area under the concentration-time curve




Maximum concentration


Cytochrome P450


Drug-drug interactions






Oral bioavailability


Fraction absorbed into gut wall


Fraction reaching gut wall that escapes intestinal first-pass metabolism


Fraction reaching liver that escapes hepatic first-pass metabolism


Parameter that quantifies the magnitude of the recycling (inter-conversion) process


First order conditional estimation method with interaction


3-hydroxy-3-methylglutaryl-coenzyme A


Monte-Carlo importance sampling assisted by mode a posteriori estimation




In vitro - in vivo extrapolation


Inverse-Wishart distribution


Low-density lipoprotein


Limit of quantification


Maximum a posteriori


Markov chain Monte Carlo


Organic anion transporting polypeptide


Physiologically-based pharmacokinetic




Relative standard error


Single nucleotide polymorphism


Simvastatin (lactone form)


Simvastatin acid (acid form)


Visual predictive check



N.T. is the recipient of a PhD grant jointly awarded by the University of Manchester and Eli Lilly and Company. A.R-H. is an employee of the University of Manchester and parttime secondee to Simcyp Limited (a Certara Company). Simcyp’s research is funded by a consortium of pharma companies. The authors would like to acknowledge the fruitful comments and discussions made by Dr Michael Gertz, Roche and by the members of the Centre for Applied Pharmacokinetic Research at the University of Manchester. The authors would also like to thank Dr Joe Polli for the provision of individual SV and SVA data from Polli et al., 2013 [22].

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Nikolaos Tsamandouras
    • 1
  • Gemma Dickinson
    • 2
  • Yingying Guo
    • 2
  • Stephen Hall
    • 2
  • Amin Rostami-Hodjegan
    • 1
    • 3
  • Aleksandra Galetin
    • 1
  • Leon Aarons
    • 1
  1. 1.Centre for Applied Pharmacokinetic Research, Manchester Pharmacy SchoolThe University of ManchesterManchesterUK
  2. 2.Eli Lilly and CompanyIndianapolisUSA
  3. 3.Simcyp Limited, Blades Enterprise CentreSheffieldUK

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