title: Imatinib Pharmacokinetics in a Large Observational Cohort of Gastrointestinal Stromal Tumour Patients.
abstract: Low trough imatinib concentration (Cmin) values have been associated with poor clinical outcomes in gastrointestinal stromal tumour (GIST) patients. This study describes the pharmacokinetics of imatinib in a large cohort of GIST patients in routine clinical care.
  
  
  
  An observational study was performed in imatinib-treated GIST patients. Patient and tumour characteristics were derived from the Dutch GIST Registry and medical records. Imatinib concentrations were measured by liquid chromatography with tandem mass spectrometry. The analyses included the occurrence of a low imatinib Cmin(<1000 µg/L), the change in the Cminover time and the correlation between exposure and response.
  
  
  
  In total, 421 plasma samples were available from 108 GIST patients. Most patients (79.6 %) received an imatinib dose of 400 mg. The inter- and intrapatient variabilities in Cminwere 54 and 23 %, respectively. In the first steady-state sample, 44.4 % of patients presented with Cminvalues <1000 µg/L; 32.4 % of patients had values <1000 µg/L in >75 % of their samples. Only 33.3 % of patients had Cminvalues ≥1000 µg/L in all measured samples. No decrease in Cminover time was found (P > 0.05). Fifty-seven (91.9 %) of 62 palliative-treated patients had a tumour response (median Cmin1271 µg/L). Five palliative patients (8.1 %) did not respond (median Cmin920 µg/L). Given the limited number of non-responders in this cohort, no statistically significant association with clinical benefit could be demonstrated.
  
  
  
  In routine clinical care, one third of GIST patients are systematically underexposed with a fixed dose of imatinib. Prospective clinical studies are needed to investigate the value of Cmin-guided imatinib dosing in GIST patients.
authors.affiliation: Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. s.farag@nki.nl.
authors.forename: Sheima
authors.identifier: 0000-0002-1634-5033
authors.initials: S
authors.lastname: Farag
authors.affiliation: Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Remy B
authors.initials: RB
authors.lastname: Verheijen
authors.affiliation: Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Martijn Kerst
authors.affiliation: Department of Gastroenterology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Annemiek
authors.initials: A
authors.lastname: Cats
authors.affiliation: Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Neeltje
authors.initials: N
authors.lastname: Steeghs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000453:epidemiology; D046152:Gastrointestinal Stromal Tumors / Q000097:blood* / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D000068877:Imatinib Mesylate / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D012042:Registries; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate