Development and Application of a Mechanistic Pharmacokinetic Model for Simvastatin and its Active Metabolite Simvastatin Acid Using an Integrated Population PBPK Approach
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.
KEY WORDS“drug-drug interactions” “OATP1B1” “PBPK” “population model” “simvastatin”
Area under the concentration-time curve
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
Monte-Carlo importance sampling assisted by mode a posteriori estimation
In vitro - in vivo extrapolation
Limit of quantification
Maximum a posteriori
Markov chain Monte Carlo
Organic anion transporting polypeptide
Relative standard error
Single nucleotide polymorphism
Simvastatin (lactone form)
Simvastatin acid (acid form)
Visual predictive check
ACKNOWLEDGMENTS AND DISCLOSURES
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 .
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