title: A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients.
abstract: OBJECTIVE
  Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib.
  
  
  METHODS
  Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging.
  
  
  RESULTS
  After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm(3) increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed.
  
  
  CONCLUSIONS
  This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level - clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.
authors: Department of Medical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors: Karel
authors: K
authors: Eechoute
authors: Martin N
authors: MN
authors: Fransson
authors: An K
authors: AK
authors: Reyners
authors: Floris A
authors: FA
authors: de Jong
authors: Alex
authors: A
authors: Sparreboom
authors: Winette T A
authors: WT
authors: van der Graaf
authors: Lena E
authors: LE
authors: Friberg
authors: Gaia
authors: G
authors: Schiavon
authors: Erik A C
authors: EA
authors: Wiemer
authors: Jaap
authors: J
authors: Verweij
authors: Walter J
authors: WJ
authors: Loos
authors: Ron H J
authors: RH
authors: Mathijssen
authors: Ugo
authors: U
authors: De Giorgi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate