The influence of gastrointestinal resection on sunitinib exposure in GIST patients

10547 Background: GIST patients often have an altered anatomy of the GI tract due to either primary resection of the tumor or palliative surgery. It is unknown whether such GI resections affect the exposure to sunitinib and its active metabolite SU12662. Previous studies showed that the exposure to imatinib and nilotinib was decreased in GIST patients with prior major gastrectomy. Therefore, we postulated that GI resections might similarly affect sunitinib exposure. Methods: A retrospective analysis was performed to assess the effect of GI resections on sunitinib exposure. Pharmacokinetic data from 305 GIST patients included in 4 phase I-II trials were analyzed. Patients were subdivided into 6 groups according to prior GI surgery: 1)Major gastrectomy: 2)Partial gastrectomy: 3)Small bowel resection: 4)Combination of gastrectomy and small bowel resection: 5)Colon resection and 6)Controls with no prior GI surgery. Patients with uncertain GI resections were excluded. Dose normalized exposure (AUC0-24hr) of sunitinib and SU12662 was estimated with a population PK approach using NONMEM. Analysis of covariance was performed to test for significant differences in AUC between each of the subgroups and controls. Results: The geometric mean of total exposure to sunitinib and SU12662 was decreased by 21% and 28% in subgroup 4, (n=8; sunitinib: 931 ng*hr/mL (95%CI;676-1283) and SU12662: 354 ng*hr/mL (95%CI;174-720)) compared to controls (n=63; sunitinib: 1177 ng*hr/mL (95%CI;1097-1263) and SU12662: 491 ng*hr/mL (95%CI;435-555)), with the differences being significant (p