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Open Access Research article

Effect of gastrointestinal resection on sunitinib exposure in patients with GIST

Djoeke de Wit1, Nielka P van Erp2*, Reza Khosravan3, Robin Wiltshire4, Randy Allred3, George D Demetri5, Henk-Jan Guchelaar1 and Hans Gelderblom6

Author Affiliations

1 Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands

2 Department of Clinical Pharmacy, Radboud University Medical Center, Route 864, Postbus 9101, 6500 HB Nijmegen, The Netherlands

3 Pfizer Inc, San Diego, CA, USA

4 Pfizer Inc, Tadworth, Surrey, England

5 Department of Medical Oncology/Solid Tumor Oncology, Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

6 Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

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BMC Cancer 2014, 14:575  doi:10.1186/1471-2407-14-575

Published: 8 August 2014

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.

Conclusion

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.

Keywords:
Sunitinib; Exposure; Gastrointestinal resection; GIST