title: Effect of gastrointestinal resection on sunitinib exposure in patients with GIST.
abstract: BACKGROUND
  GIST patients often undergo GI-surgery. Previous studies have shown that imatinib and nilotinib exposures were decreased in GIST patients with prior major gastrectomy. We investigated whether major gastrectomy influences the exposure to sunitinib and its active metabolite SU12662.
  
  
  METHODS
  Pharmacokinetic data from 305 GIST patients included in 4 phase I-III trials were analyzed. Patients were subdivided into 6 groups according to their prior GI-surgery. Apparent clearance (CL/F) and dose-corrected steady-state plasma exposures (AUC24,ss) of sunitinib and SU12662 were estimated using a population PK approach. ANCOVA was performed to test for differences in AUC24,ss and CL/F between each surgery subgroup and controls.
  
  
  RESULTS
  Major gastrectomy did not influence sunitinib or SU12662 exposure. The geometric mean of sunitinib and SU12662 AUC24,ss was decreased by 21% and 28% in patients with both gastrectomy and small bowel resection (n = 8) compared to controls (n = 63) for sunitinib (931 ng hr/mL (95%-CI; 676-1283) versus 1177 ng hr/mL (95%-CI; 1097-1263); p < 0.05) and SU12662 (354 ng hr/mL (95%-CI; 174-720) versus 492 ng hr/mL (95%-CI; 435-555); p < 0.05). No significant differences in exposure were observed in each of the other subgroups versus controls.
  
  
  CONCLUSIONS
  In contrast to previous results for imatinib and nilotinib, gastrectomy alone does not influence sunitinib or SU12662 exposure. This should be taken into account for the treatment of gastrectomized GIST patients with TKIs. In patients who had undergone both gastrectomy and small bowel resection, sunitinib and SU12662 exposures are significantly, although clinically not relevantly, decreased.
authors.forename: Djoeke
authors.initials: D
authors.lastname: de Wit
authors.affiliation: Department of Clinical Pharmacy, Radboud University Medical Center, Route 864, Postbus 9101, 6500 HB Nijmegen, The Netherlands. Nielka.vanErp@radboudumc.nl.
authors.forename: Nielka P
authors.initials: NP
authors.lastname: van Erp
authors.forename: Reza
authors.initials: R
authors.lastname: Khosravan
authors.forename: Robin
authors.initials: R
authors.lastname: Wiltshire
authors.forename: Randy
authors.initials: R
authors.lastname: Allred
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D005260:Female; D005743:Gastrectomy / Q000009:adverse effects; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000601:surgery*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000601:surgery*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077210:Sunitinib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C544393:SU 12662; D000077210:Sunitinib
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