title: Pharmacologic activity and pharmacokinetics of metabolites of regorafenib in preclinical models.
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 IC50at human and murine VEGFR2, suggesting that regorafenib and M-2 are the primary contributors to the pharmacologic activity of regorafenib in vivo.
authors.affiliation: Drug Discovery, Bayer Pharma AG, Müllerstraße 178, Berlin, 13353, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Zopf
authors.affiliation: Experimental Pharmacology & Oncology GmbH, Robert-Rössle-Str. 10, Berlin-Buch, 13125, Germany.
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.affiliation: Shakti Bioresearch, 1 Bradley Road, STE 401, Woodbridge, Connecticut, 06525.
authors.forename: Ajay
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: Pharmacokinetic Imaging Consulting & Autoradiography Services, Halverscheid 13, D-58553, Halver, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Steinke
authors.affiliation: Drug Discovery, Bayer Pharma AG, Müllerstraße 178, Berlin, 13353, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Thierauch
authors.affiliation: Drug Discovery, Bayer Pharma AG, Müllerstraße 178, Berlin, 13353, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Diefenbach
authors.affiliation: Bayer HealthCare Pharmaceuticals, 100 Bayer Blvd, Whippany, New Jersey, 07981.
authors.forename: Scott
authors.initials: S
authors.lastname: Wilhelm
authors.affiliation: Drug Discovery, Bayer Pharma AG, Müllerstraße 178, Berlin, 13353, Germany.
authors.forename: Frank-Thorsten
authors.initials: FT
authors.lastname: Hafner
authors.affiliation: Drug Discovery, Bayer Pharma AG, Müllerstraße 178, Berlin, 13353, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gerisch
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib; D011494:Protein Kinases
keywords: Antitumor activity; metabolite; multikinase inhibitor; pharmacology; regorafenib