title: Elevated prothrombin time/international normalized ratio associated with concurrent administration of regorafenib and warfarin in a patient with advanced colorectal cancer.
abstract: BACKGROUND
  Regorafenib and its metabolites may inhibit the activities of several CYP or UDP-glucuronosyltransferase isoforms, including that of CYP2C9. Therefore, pharmacological agents that are CYP2C9 substrates may show elevated circulating levels and enhanced drug efficacy when concurrently used with regorafenib. Previous studies showed that the area under the plasma concentration-time curve of warfarin, which is the substrate for CYP2C9, increased upon co-administration of regorafenib. However, there are no reports indicating that the anticoagulant effects of warfarin increased upon co-administration of regorafenib.
  
  
  METHODS
  We report a case of a 76-year-old man with liver metastasis of colon cancer. He was treated with regorafenib at a dosage of 120 mg daily on days 1 to 21 every 4 weeks as a third-line therapy. He had a history of acute myocardial infarction and had taken 2 mg warfarin daily. Three weeks after the treatment began, PT/INR values markedly increased, although there was no hemorrhage. Administration of regorafenib and warfarin was discontinued, and then PT/INR rapidly decreased. Warfarin administration was restarted (0.5 mg daily) and the dose was increased up to 1.5 mg daily. The patient's PT/INR values exhibited a tendency to increase when concurrently used with regorafenib, the dose of which was reduced to 80 mg daily on days 1 to 14 every 3 weeks at a physician's discretion.
  
  
  CONCLUSIONS
  The clinical course of this patient suggested that PT/INR might increase during concurrent use of warfarin and regorafenib. Therefore, PT/INR should be periodically monitored during the concurrent use of warfarin and regorafenib.
authors.affiliation: Department of Pharmacy, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kitade
authors.affiliation: Department of Pharmacy, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Hiromasa-Yamasaki
authors.affiliation: Department of Pharmacy, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hokkoku
authors.affiliation: Department of Pharmacy, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan.
authors.forename: Mitsue
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Gastroenterology, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan ; Outpatient Cancer Chemotherapy Center, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan.
authors.forename: Masuo
authors.initials: M
authors.lastname: Nakai
authors.affiliation: Outpatient Cancer Chemotherapy Center, Houju Memorial Hospital, 11-71, Midorigaoka, Nomi-shi, Ishikawa 923-1226 Japan ; Department of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934 Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
keywords: Colorectal cancer; PT/INR; Regorafenib; Warfarin