CCR 20th Anniversary Commentary: Determining a Pharmacokinetic/ Pharmacodynamic Relationship for Sunitinib-A Look Back

摘要

The article by Mendel and colleagues, published in the January 1, 2003, issue of Clinical Cancer Research, described their novel preclinical approach to developing a thorough understanding of the exposure-activity relationship for sunitinib, a multitargeted receptor tyrosine kinase inhibitor being developed for oncology therapy. This work successfully set exposure guidelines to identify a biologically active dose in early clinical trials. Sunitinib (SU11248), which was discovered at SUGEN/Phar-mada in 2000 and became part of the Pfizer portfolio following completion of the acquisition of Pharmacia by Pfizer in 2003, is a small-molecule, receptor tyrosine kinase (RTK) inhibitor that was designed to selectively target the class III/V RTKs, including the vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), FLT3, and KIT. By virtue of targeting these RTKs, it was expected that sunitinib would exhibit a dual mechanism to benefit patients with cancer, first, direct antitumor activity against tumors that express and rely on one or more targets for tumor cell proliferation and/or survival [e.g., mutated KIT in gastrointestinal stromal tumors (GIST) and mutated FLT3 in acute myelogenous leukemia (AML)], and second, to provide potent antiangiogenic activity by targeting VEGFR2 and PDGFRfS. Sunitinib, under the commercial name Sutent, initially received marketing approval from the FDA in 2006 for the treatment of advanced renal cell carcinoma and GIST after disease progression on, or intolerance to, imatinib mesylate. It has subsequently been approved to treat progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease. The studies reported by Mendel and colleagues (1) incorporate a novel approach focused on understanding the pharmacokinetic/ pharmacodynamic (PK/PD) relationship for the efficacy of sunitinib in preclinical models that could be used to help guide early clinical development, including selection of a biologically active clinical dose rather than the more traditional maximum tolerated dose.