title: Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers.
abstract: OBJECTIVE
  Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). The aim of this study was to investigate the absorption and distribution kinetics of imatinib in healthy Iranian volunteers using nonlinear mixed effects modeling (NLMEM) to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters after oral administration.
  
  
  METHODS
  This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study after administering a single dose of 200 mg of each formulation. Imatinib concentrations were quantified using a validated liquid chromatography method. To simultaneously describe the imatinib pharmacokinetic profiles obtained with both formulations, a population pharmacokinetic model was applied to data using SAEM algorithm implemented in MONOLIX, whilst simulations were used by numerical solving of ordinary differential equations to calculate secondary parameters in individuals for bioequivalence studies.
  
  
  RESULTS
  According to goodness-of-fit criteria, a two-compartment open model with sequential zero- then first-order absorption and first-order elimination was used as the structural pharmacokinetic model. Inter-individual variability (IIV) was considered for all parameters. Typical population estimates (% IIV) were fraction of the drug absorbed with a zero-order kinetic (Fr) of 0.153 (47.9 %) in period (Tk0) of 0.714 h (47.4 %), first-order absorption rate constant (k a) of 0.94 h(-1)(31.2 %), oral clearance of 19 L/h (27.9 %), central volume of distribution (V c/F) of 139 L (21.5 %), apparent peripheral volume of distribution (V p/F) of 130 L (29.7 %) and the apparent inter-compartment clearance (Q/F) of 29.6 L/h (41.8 %). Body mass index (BMI) was the only covariate found to significantly affect V p /F. The coefficient of variation for intra-individual plasma exposure (AUC0-∞) was 27.8 %.
  
  
  CONCLUSIONS
  Analyses using NLMEM for imatinib exhibited absorption complexities such as two input rates and medium to high intra-individual variability in drug exposure.
authors.affiliation: Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14155-651, Iran.
authors.forename: Ali-Akbar
authors.initials: AA
authors.lastname: Golabchifar
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
authors.forename: Saeed
authors.initials: S
authors.lastname: Rezaee
authors.affiliation: Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14155-651, Iran.
authors.forename: Nahid Mobarghei
authors.initials: NM
authors.lastname: Dinan
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Abbas
authors.initials: A
authors.lastname: Kebriaeezadeh
authors.affiliation: Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14155-651, Iran. rouini@tums.ac.ir.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Rouini
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018592:Cross-Over Studies; D005260:Female; D065569:Gastrointestinal Absorption / Q000502:physiology; D064368:Healthy Volunteers; D006801:Humans; D000068877:Imatinib Mesylate / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007492:Iran; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000378:metabolism*; D013810:Therapeutic Equivalency; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate