title: Febuxostat for management of tumor lysis syndrome including its effects on levels of purine metabolites in patients with hematological malignancies - a single institution's, pharmacokinetic and pilot prospective study.
abstract: OBJECTIVE
  Tumor lysis syndrome (TLS) is a life-threatening oncological emergency, and control of serum uric acid level (S-UA) is most important. In this single-institution, short-term and pilot prospective study, the efficacy of a new xanthine oxidase inhibitor, febuxostat, as an alternative to conventional allopurinol, including its effects on hypoxanthine and xanthine, was evaluated in 10 consecutive patients with hematological malignancies at intermediate risk for TLS.
  
  
  METHODS
  Febuxostat at 40 mg (n=7) or 60 mg (n=3) daily was administered according to renal function, and induction chemotherapy was started within 24 h. The primary end-point was the reduction of S-UA to ≤ 7.5 mg/dl by day 5.
  
  
  RESULTS
  The median S-UA at base-line was 8.0 mg/dl (range=3.2-10.6 mg/dl). The median S-UA on day 5 after chemotherapy was 3.3 mg/dl (range=1.1-5.8 mg/dl) (p<0.0001, by paired t-test), indicating successful control of S-UA during chemotherapy. All patients achieved S-UA ≤ 7.5 mg/dl. A simultaneous decrease in serum creatinine and increase in estimated glomerular filtration rate were seen. Serum hypoxanthine and xanthine levels (as the consequence of inhibition of xanthine oxidase) were elevated along with the decrease in S-UA. Xanthine level was elevated higher compared to hypoxanthine level and reached the level reported to cause xanthine nephropathy, but no advance of renal impairment was observed. Serum febuxostat concentrations at 2 h after administration were 891.8 ± 285.0 ng/ml (mean ± SE) for the 40-mg dose and 770.6 ± 242.7 ng/ml for the 60-mg dose (p=0.80, unpaired t-test), showing no accumulation in patients with renal impairment. No febuxostat-related adverse reactions were noted. No patients experienced progressive TLS.
  
  
  CONCLUSIONS
  Febuxostat is promising for the management of TLS of an intermediate-risk patient and further observation and reevaluation regarding xanthine nephropathy should be performed.
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Takai
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan tyamauch@u-fukui.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ookura
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tai
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kishi
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000368:Aged; D000493:Allopurinol / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069465:Febuxostat; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D019271:Hypoxanthine / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015275:Tumor Lysis Syndrome / Q000188:drug therapy / Q000517:prevention & control*; D014527:Uric Acid / Q000097:blood*; D019820:Xanthine / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013844:Thiazoles; D000069465:Febuxostat; D019820:Xanthine; D014527:Uric Acid; D019271:Hypoxanthine; D000493:Allopurinol; D003404:Creatinine; D014969:Xanthine Oxidase
keywords: Tumor lysis syndrome; chemotherapy; febuxostat; hematological malignancy; hyperuricemia