A phase I mass-balance study to evaluate the metabolism and excretion of [14C]-sunitinib (SU11248) in healthy male subjects
Authors: Carlo Bello, Hai-Zhi Bu, Shem Patyna, Ping Kang, Geoffrey Peng, William Pool, John Smeraglia, Laurie Sherman, May Garrett, Karen Klamerus
Journal: Cancer Research (2007)

LB-354  Introduction: Preclinical data from rats and monkeys indicate that sunitinib malate (an oral, multitargeted receptor tyrosine kinase [RTK] inhibitor of VEGFRs, PDGFRs and other RTKs with direct antitumor and antiangiogenic activity) and its metabolites are mainly excreted in feces, with urinary excretion as a minor route of elimination. An open-label, mass-balance study was conducted in healthy male subjects to characterize: the primary routes of elimination of sunitinib and drug-related materials; the pharmacokinetics of total radioactivity, and plasma sunitinib and SU12662 (its primary desethylated active metabolite); and to identify the metabolites of sunitinib in plasma, urine, and/or feces if possible.  Methods: On day 1, 8 subjects (>18 years) received a single, oral 50-mg sunitinib capsule containing approximately 100 µCi of [14C]-sunitinib. Serial blood samples and urine and feces were collected at specified times over 21 days.  Results: Six subjects were evaluable for pharmacokinetics and 8 for safety. The mean cumulative recovery in feces (61%) and urine (16%) accounted for approximately 77% of the radioactive dose over the 21 days, with the majority of recovery in the first 7 days. Fecal excretion was the major route of elimination of sunitinib and drug-related materials being 4-fold greater than the urinary route. Sunitinib and SU12662 were the primary components identified in plasma, feces, and urine. The only other identifiable component in urine was the N-oxide SU12487; however, its levels were too low to be detected in metabolite profiling evaluations. As determined by metabolite profiling, sunitinib and SU12662 represented 71% and 20.5%, respectively, of radioactivity in the pooled plasma samples (total, 91.5%) and 44.9% and 41.5%, respectively, of radioactivity in the pooled urine samples (total, 86.4%). Two other minor metabolites were radiochemically quantifiable in feces only. The mean (%CV) AUCinf and Cmax as measured by LC-MS-MS for sunitinib were 1063 (25) ng*hr/mL and 24.4 (16) ng/mL, respectively; for SU12662, these were 593 (15) ng*hr/mL and 6.2 (29) ng/mL, respectively. There were no clinically significant (grade 3 or 4) adverse events, deaths, serious adverse events, or withdrawals due to adverse events reported in this study. All treatment- and non-treatment-related adverse events were grade 1 and resolved.  Conclusions: Data from this phase I mass-balance study of healthy human subjects are consistent with preclinical models. Sunitinib and SU12662 were the only measurable components in plasma; other minor metabolites were identified only in feces. Plasma pharmacokinetics of sunitinib and SU12662 in the study subjects were consistent with the results observed in previous single-dose studies with non-radiolabeled drug. These results further establish fecal excretion as the major route of elimination of sunitinib.