Abstract
PurposeTo evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated.MethodsFour healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.7 MBq) [14C]regorafenib. Plasma concentrations of parent drug were derived from HPLC–MS/MS analysis and total radioactivity from liquid scintillation counting (LSC). Radiocarbon analyses used HPLC with fraction collection followed by LSC for all urine samples, plasma, and fecal homogenate extracts. For the in vitro study, [14C]regorafenib was incubated with human hepatocytes and analyzed using HPLC–LSC and HPLC–HRMS/MS.ResultsRegorafenib was the major component in plasma, while metabolite M-2 (pyridine N-oxide) was the most prominent metabolite. Metabolites M-5 (demethylated pyridine N-oxide) and M-7 (N-glucuronide) were identified as minor plasma components. The mean concentration of total radioactivity in plasma/whole blood appeared to plateau at 1–4 h and again at 6–24 h post-dose. In total, 90.5% of administered radioactivity was recovered in the excreta within a collection interval of 12 days, most of which (71.2%) was eliminated in feces, while excretion via urine accounted for 19.3%. Regorafenib (47.2%) was the most prominent component in feces and was not excreted into urine. Excreted metabolites resulted from oxidative metabolism and glucuronidation.ConclusionsRegorafenib was eliminated predominantly in feces as well as by hepatic biotransformation. The multiple biotransformation pathways of regorafenib decrease the risk of pharmacokinetic drug–drug interactions.
Highlights
Regorafenib is an orally active multikinase inhibitor that blocks the activity of a broad range of protein kinases involved in tumor angiogenesis, oncogenesis, metastasis, and tumor immunity [1,2,3]
Carbon-14-labeled regorafenib, [14C]BAY 73-4506, 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-[14C] carboxamide, at a specific activity of 2.53 MBq/mg and radiochemical purity of 99.4% as assessed by high-performance liquid chromatography (HPLC) with radioactivity detection, stable isotope-labeled regorafenib, [2H315N]BAY 73-4506, 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl} amino)-3-fluorophenoxy]-N-[2H3]methylpyridine-2-carbox[15N]amide, and [ 14C]-labeled metabolite M-2 were synthesized by the isotope chemistry group at the Department of Drug Metabolism and Pharmacokinetics, Bayer AG (Wuppertal, Germany)
Four healthy male subjects were enrolled in the study, received a single dose of 120 mg regorafenib blended with approximately 100 μCi [14C]regorafenib as solution, and completed the study according to protocol
Summary
Regorafenib is an orally active multikinase inhibitor that blocks the activity of a broad range of protein kinases involved in tumor angiogenesis, oncogenesis, metastasis, and tumor immunity [1,2,3]. Antitumor activity with an acceptable safety profile was observed in early clinical studies. In patients with a range of solid tumors [4,5,6,7,8]. Subsequent phase III studies demonstrated clinical benefit in patients with refractory metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and hepatocellular carcinoma [9,10,11,12], resulting in the approval of regorafenib (160 mg daily for the first 3 weeks of a 4-week cycle) for the treatment of these cancers. The plasma concentration–time profiles of regorafenib, M-2, and M-5 at steady state exhibited multiple maxima, with an
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
