Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers

Abstract

IntroductionLesinurad 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.MethodsTwo 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.ResultsMild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration–time curve by 34%, 54%–65%, and 102%, respectively. Lesinurad plasma Cmax was 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.ConclusionLesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment.

Determination of lesinurad in rat plasma by a UHPLC–MS/MS assay

“…3 . A double-peak phenomenon was observed in the mean plasma concentration versus time curve after oral administration of lesinurad, which is different from the results obtained from studies in gout patients [ 17 ] or healthy adults [ 18 , 19 ].…”

Effects of uric acid-lowering therapy in patients with chronic kidney disease: A meta-analysis

“…The renoprotective effects from the inhibition of reactive oxygen species formation by xanthine oxidase inhibitors have not been discounted [ 53 ]. Among other uric acid-lowering agents, such as benzbromarone, lesinurad [ 54 ], and canagliflozin (sodium glucose transporter 2) [ 55 ], whether there is heterogeneity in terms of their effects on kidney and cardiovascular protection in patients with CKD requires confirmation with further studies. Third, the absence of patient-specific data and the varying design of the included studies are limitations of many meta-analyses; in an effort to nullify these factors, we included only RCTs.…”

Clinical efficacy and safety of dotinurad, a novel selective urate reabsorption inhibitor, in Japanese hyperuricemic patients with or without gout: randomized, multicenter, double-blind, placebo-controlled, parallel-group, confirmatory phase 2 study

“…Lesinurad, bucolome, and probenecid reportedly have attenuated serum uric acid lowering effects in patient with renal dysfunction [1,17]. In contrast, in the subgroup analysis of this study that examined renal function at baseline, the serum uric acid lowering effect of dotinurad in patients with moderate renal dysfunction (eGFR ≥ 30 to < 60 mL/min/1.73 m 2 ) was comparable those with mild dysfunction (eGFR ≥ 60 to < 90 mL/min/1.73 m 2 ) and normal function (eGFR ≥ 90 mL/min/1.73 m 2 ) ( Table 5).…”