Akimitsu Maeda1, Kei Irie2,3, Hitoshi Ando4, Ayako Hasegawa5, Hiroya Taniguchi6, Shigenori Kadowaki6, Kei Muro6, Masahiro Tajika7, Masahiro Aoki8, Kazuhide Inaguma5, Masaki Kajita5, Akio Fujimura9, Shoji Fukushima3. 1. Department of Pharmacy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. m.akimitsu@aichi-cc.jp. 2. Department of Pharmacy, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, Kobe, Japan. 3. Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, Kobe, Japan. 4. Department of Cellular and Molecular Function Analysis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. 5. Department of Pharmacy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. 6. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 7. Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan. 8. Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan. 9. Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan.
Abstract
PURPOSE: The ability of predicting severe adverse reactions caused by regorafenib is important. We evaluated regorafenib concentrations for adverse reaction risks and assessed the relevance of laboratory values and gene polymorphisms. METHODS: A total of 28 Japanese cancer patients who were treated with regorafenib were evaluated for the steady state of serum regorafenib concentrations and adverse reactions for 28 days. In addition, we determined the association of regorafenib concentrations with ABCG2 and OATP1B1 polymorphisms, which are regorafenib transporters. RESULTS: Regorafenib concentrations were significantly higher in the group with Grade 2 or higher total bilirubin elevation and thrombocytopenia compared with the group with grades 0 or 1 [3.45 (2.18-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.01 and 3.45 (2.12-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.02, respectively]. A strong association was noted between serum regorafenib concentrations and total bilirubin levels, but the physical and genetic factors predicting regorafenib pharmacokinetics could not be clarified. CONCLUSIONS: Regorafenib concentrations were associated with total bilirubin elevation and thrombocytopenia. Total serum bilirubin could be a useful marker when estimating regorafenib pharmacokinetics.
PURPOSE: The ability of predicting severe adverse reactions caused by regorafenib is important. We evaluated regorafenib concentrations for adverse reaction risks and assessed the relevance of laboratory values and gene polymorphisms. METHODS: A total of 28 Japanese cancerpatients who were treated with regorafenib were evaluated for the steady state of serum regorafenib concentrations and adverse reactions for 28 days. In addition, we determined the association of regorafenib concentrations with ABCG2 and OATP1B1 polymorphisms, which are regorafenib transporters. RESULTS:Regorafenib concentrations were significantly higher in the group with Grade 2 or higher total bilirubin elevation and thrombocytopenia compared with the group with grades 0 or 1 [3.45 (2.18-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.01 and 3.45 (2.12-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.02, respectively]. A strong association was noted between serum regorafenib concentrations and total bilirubin levels, but the physical and genetic factors predicting regorafenib pharmacokinetics could not be clarified. CONCLUSIONS:Regorafenib concentrations were associated with total bilirubin elevation and thrombocytopenia. Total serum bilirubin could be a useful marker when estimating regorafenib pharmacokinetics.
Authors: Elena De Mattia; Erika Cecchin; Michela Guardascione; Luisa Foltran; Tania Di Raimo; Francesco Angelini; Mario D'Andrea; Giuseppe Toffoli Journal: World J Gastroenterol Date: 2019-08-07 Impact factor: 5.742