title: Development and Application of a Mechanistic Pharmacokinetic Model for Simvastatin and its Active Metabolite Simvastatin Acid Using an Integrated Population PBPK Approach.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Stopford Building, Room 3.32, Oxford Road, Manchester, M13 9PT, UK, nikolaos.tsamandouras@manchester.ac.uk.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tsamandouras
authors.forename: Gemma
authors.initials: G
authors.lastname: Dickinson
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.forename: Stephen
authors.initials: S
authors.lastname: Hall
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
mesh_terms: D065767:Activation, Metabolic; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000627:therapeutic use; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; C063287:simvastatin acid; D019821:Simvastatin