Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males

Abstract

Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.

Keywords: URAT1; clearance; food effect; single and multiple doses; urate lowering; urinary excretion.

Figure 1

Plasma lesinurad concentration profiles. (A) and median percent change from baseline in serum uric acid profiles following single doses of lesinurad in healthy male subjects (B). Notes: The points before “0” represent the pre-dose values for all groups.

Figure 2

Median percent changes from baseline (time-matched, day −1) serum concentrations of urate following once-daily oral doses of lesinurad for 10 days. Notes: The top x-axis labels refer to the hours of that day, where “0” of the next day is the same as 24 hours of the previous day. Abbreviation: IR, immediate release.

Figure 3

Median plasma concentration profiles from 0 to 24 hours post-dose following single doses of lesinurad: tablet versus capsule in healthy fed male subjects. Abbreviation: IR, immediate release.

Figure 4

Dose linearity and proportionality of lesinurad under fasted (5–400 mg) or fed (100–600 mg) conditions in healthy subjects (A), and correlation between plasma lesinurad exposure or amount excreted in urine and serum uric acid-lowering effect (B). Abbreviations: AUC, area under the plasma concentration–time curve; CI, confidence interval; C_max, maximum observed plasma concentration.