title: Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia.
abstract: OBJECTIVE
  We evaluated the population pharmacokinetics (PPK) and exposure-response relationship of imatinib mesylate in Iranian patients with chronic myeloid leukemia (CML).This study was designed to assess steady state (SS) imatinib trough concentrations (Cmin) and pharmacokinetics parameters of imatinib in patients with CML in chronic phase after at least 12-month treatment.
  
  
  METHODS
  Plasma concentrations from a randomized controlled trial consist of 61 patients who received oral imatinib at doses ranged between 300 and 800 mg in various dosing interval, which were quantified using a validated reversed-phase high-performance liquid chromatographic method with UV detection method on different occasions at SS and evaluated using PPK model.
  
  
  RESULTS
  A one-compartment model with zero-order absorption and a lag time was sufficient in describing the concentration-time profile. Inter-individual variability (IIV) was modeled for all parameters. Oral clearance (CL/F) and the volume of distribution (V/F) were estimated to 10.8 L/h with 30 % IIV and 265 L with 53 % IIV, respectively. Inter-occasion variability (IOV) was included in CL/F (17 %) and V/F (22 %).The proportional residual error of the model was 8 %.
  
  
  CONCLUSIONS
  Simulation analysis from individual parameters shows exposure to imatinib is highly variable among patients. Imatinib trough plasma levels <1,257 ng/mL were associated with lower rates of major molecular response. Because of the wide IIV compared with IOV with imatinib in our study, trough levels may play a role in investigating instances of suboptimal response.
authors.affiliation: Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155-651, Tehran, Iran.
authors.forename: Ali-Akbar
authors.initials: AA
authors.lastname: Golabchifar
authors.forename: Saeed
authors.initials: S
authors.lastname: Rezaee
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Ghavamzadeh
authors.forename: Kamran
authors.initials: K
authors.lastname: Alimoghaddam
authors.forename: Nahid Mobarghei
authors.initials: NM
authors.lastname: Dinan
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Rouini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001499:Bayes Theorem; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D016044:Fusion Proteins, bcr-abl / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007492:Iran; D015466:Leukemia, Myeloid, Chronic-Phase / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012372:ROC Curve; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl