Abstract
Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment‐refractory metastatic colorectal cancer. In clinical studies, steady‐state exposure to the M‐2 and M‐5 metabolites of regorafenib was similar to that of the parent drug; however, the contribution of these metabolites to the overall observed clinical activity of regorafenib cannot be investigated in clinical trials. Therefore, we assessed the pharmacokinetics and pharmacodynamics of regorafenib, M‐2, and M‐5 in vitro and in murine xenograft models. M‐2 and M‐5 showed similar kinase inhibition profiles and comparable potency to regorafenib in a competitive binding assay. Inhibition of key target kinases by all three compounds was confirmed in cell‐based assays. In murine xenograft models, oral regorafenib, M‐2, and M‐5 significantly inhibited tumor growth versus controls. Total peak plasma drug concentrations and exposure to M‐2 and M‐5 in mice after repeated oral dosing with regorafenib 10 mg/kg/day were comparable to those in humans. In vitro studies showed high binding of regorafenib, M‐2, and M‐5 to plasma proteins, with unbound fractions of ~0.6%, ~0.9%, and ~0.4%, respectively, in murine plasma and ~0.5%, ~0.2%, and ~0.05%, respectively, in human plasma. Estimated free plasma concentrations of regorafenib and M‐2, but not M‐5, exceeded the IC50 at human and murine VEGFR2, suggesting that regorafenib and M‐2 are the primary contributors to the pharmacologic activity of regorafenib in vivo.
Highlights
Regorafenib is an oral multikinase inhibitor that blocks the activity of multiple protein kinases, including those involved in the regulation of tumor angiogenesis (VEGFR1, 2, and 3, and TIE-2 ), oncogenesis (KIT, RET, RAF-1, BRAF, and BRAFV600E), and the tumor microenvironment (PDGFR and FGFR) [1,2,3]
Steady-state exposure to the M-2 and M-5 metabolites of regorafenib was similar to that of the parent drug; the contribution of these metabolites to the overall observed clinical activity of regorafenib cannot be investigated in clinical trials
Given the substantial systemic exposure to the M-2 and M-5 metabolites observed in clinical trials, we investigated the pharmacokinetics and pharmacodynamics of regorafenib and these two major human metabolites in vitro and in an in vivo murine model in order to assess their potential contribution to the overall pharmacologic activity of regorafenib in humans
Summary
Regorafenib is an oral multikinase inhibitor that blocks the activity of multiple protein kinases, including those involved in the regulation of tumor angiogenesis (VEGFR1, 2, and 3, and TIE-2 ), oncogenesis (KIT, RET, RAF-1 , BRAF, and BRAFV600E), and the tumor microenvironment (PDGFR and FGFR) [1,2,3]. Early-p hase clinical studies of regorafenib demonstrated antitumor activity in a range of solid tumors [2,3,4,5,6], which has been shown to translate into clinical benefit in phase III trials in treatment-refractory metastatic CRC and GIST [7,8,9]. Results of the phase III trials have led to regulatory approval for the use of regorafenib in metastatic CRC and GIST in a number of countries globally. As regorafenib is administered orally, characterization of its biotransformation pathways and metabolite activity is of particular importance. Further oxidative biotransformation results in the demethylated N-oxide derivative M-5, a secondary metabolite of regorafenib (Fig. S1) [10]. Clinical trials in patients with advanced cancer demonstrated that total plasma exposure to each of the metabolites, M-2 and M-5, at steady state was comparable to that of the parent compound after administration of regorafenib 160 mg once daily at the approved 3 weeks on/1 week off dosing regimen [4, 5]
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