title: Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia.
abstract: OBJECTIVE
  The aim of this study was to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of lesinurad (selective uric acid reabsorption inhibitor) in combination with febuxostat (xanthine oxidase inhibitor) in patients with gout.
  
  
  METHODS
  This study was a phase IB, multicentre, open-label, multiple-dose study of gout patients with serum uric acid (sUA) >8 mg/dl following washout of urate-lowering therapy with colchicine flare prophylaxis. Febuxostat 40 or 80 mg/day was administered on days 1-21, lesinurad 400 mg/day was added on days 8-14 and then lesinurad was increased to 600 mg/day on days 15-21. sUA, urine uric acid and PK profiles were evaluated at the end of each week. Safety was assessed by adverse events, laboratory tests and physical examinations.
  
  
  RESULTS
  Initial treatment with febuxostat 40 or 80 mg/day monotherapy resulted in 67% and 56% of subjects, respectively, achieving a sUA level <6 mg/dl. Febuxostat 40 or 80 mg/day plus lesinurad 400 or 600 mg/day resulted in 100% of subjects achieving sUA <6 mg/dl and up to 100% achieving sUA <5 mg/dl. No clinically relevant changes in the PKs of either drug were noted. The combination was well tolerated.
  
  
  CONCLUSIONS
  The clinically important targets of sUA <6 mg/dl and <5 mg/dl are achievable in 100% of patients when combining lesinurad and febuxostat.
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA. rfleischmann@mcrcdallas.com.
authors: Roy
authors: R
authors: Fleischmann
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Bradley
authors: B
authors: Kerr
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Li-Tain
authors: LT
authors: Yeh
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Matt
authors: M
authors: Suster
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Zancong
authors: Z
authors: Shen
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Elizabeth
authors: E
authors: Polvent
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Vijay
authors: V
authors: Hingorani
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Barry
authors: B
authors: Quart
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Kimberly
authors: K
authors: Manhard
authors: Metroplex Clinical Research Center, Dallas, TX, Ardea Biosciences and Translational Sciences Department, Clinical Department, Regulatory Department and Biology Department, Ardea Biosciences, San Diego, CA, USA.
authors: Jeffrey N
authors: JN
authors: Miner
authors: Scott
authors: S
authors: Baumgartner
mesh_terms: D000328:Adult; D000368:Aged; D003078:Colchicine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000069465:Febuxostat; D005260:Female; D006073:Gout / Q000097:blood* / Q000188:drug therapy; D006074:Gout Suppressants / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D006801:Humans; D033461:Hyperuricemia / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D013864:Thioglycolates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D014527:Uric Acid / Q000097:blood
chemical_list: D006074:Gout Suppressants; D013844:Thiazoles; D013864:Thioglycolates; D014230:Triazoles; C000593471:lesinurad; D000069465:Febuxostat; D014527:Uric Acid; D003078:Colchicine
keywords: drug–drug interaction; febuxostat; gout; lesinurad; pharmacodynamic; pharmacokinetic; selective uric acid reabsorption inhibitor; xanthine oxidase inhibitor