title: Population pharmacokinetic analysis of simvastatin and its active metabolite with the characterization of atypical complex absorption kinetics.
abstract: OBJECTIVE
  The pharmacokinetics of simvastatin is complex with multiple peaks in the absorption phase, which cannot be adequately described by a conventional first order absorption model. The biotransformation of simvastatin into simvastatin acid, an active metabolite, is reversible. This study evaluated the pharmacokinetics of simvastatin and simvastatin acid, focusing on the absorption kinetics.
  
  
  METHODS
  Data were collected from three bioequivalence studies, in which subjects were administered 60 mg simvastatin, and from one crossover study, in which subjects were administered two doses randomly selected from 10, 20, 30, 40 to 80 mg simvastatin with washout period. The pharmacokinetics of simvastatin was assessed in 133 healthy males. Plasma concentrations of simvastatin and simvastatin acid were measured in 2,182 and 2,130 samples, respectively, and the pharmacokinetic data were analyzed using NONMEM.
  
  
  RESULTS
  The time course of changes in the plasma simvastatin concentration was best described by a two-compartment linear model with three parallel absorption processes, each of which consisted of mixed zero-and first order absorption. Additions of inter-occasional variability to the absorption parameters significantly improved the model's fit. The disposition parameter estimates were significantly different when different absorption models were applied, indicating the importance of the appropriate absorption modeling. Pharmacokinetic modeling preferred the inter-conversion between simvastatin and simvastatin acid.
  
  
  CONCLUSIONS
  A pharmacokinetic model describing the complex, multiple peak, absorption kinetics of simvastatin was formulated using three parallel, mixed zero and first-order absorptions. This type of absorption model may be applicable to other drugs that show irregular, multiple-peak concentrations during their absorption phase.
authors.affiliation: Department of Anesthesiology, Ulsan University College of Medicine Asan Medical Center, Pungnap-2-dong, 88 Olympic-ro 43-gil, Sonpa-gu, Seoul, 138-736, Korea.
authors.forename: Seok-Joon
authors.initials: SJ
authors.lastname: Jin
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Cho
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Jung
authors.forename: Unjib
authors.initials: U
authors.lastname: Kim
authors.forename: Sangmin
authors.initials: S
authors.lastname: Choe
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Ghim
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D006801:Humans; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D000924:Anticholesteremic Agents; C063287:simvastatin acid; D019821:Simvastatin