title: Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers.
abstract: BACKGROUND
  Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function.
  
  
  METHODS
  Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60-89 mL/min; N=8), moderate (eCrCl 30-59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data.
  
  
  RESULTS
  Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration-time curve by 34%, 54%-65%, and 102%, respectively. Lesinurad plasmaCmaxwas unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects.
  
  
  CONCLUSIONS
  Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment.
authors.affiliation: AstraZeneca LP, Gaithersburg, MD.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Shakti
authors.initials: S
authors.lastname: Valdez
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lee
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Zancong
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate; D006074:Gout Suppressants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D007674:Kidney Diseases / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D065667:Renal Elimination; D012720:Severity of Illness Index; D013864:Thioglycolates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000097:blood / Q000652:urine
chemical_list: D015415:Biomarkers; D006074:Gout Suppressants; D013864:Thioglycolates; D014230:Triazoles; C000593471:lesinurad; D014527:Uric Acid; D003404:Creatinine
keywords: lesinurad; pharmacodynamics; pharmacokinetics; renal function; serum urate