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.

Uric acid transporter inhibitors for gout

“…Patients given the parent compound experienced a profound uric acid lowering effect. This effect was due to drug-mediated alterations in fractional excretion of uric acid [43]. This result suggested renal transporter inhibition as the mechanism.…”

“…The URAT1 inhibitor probenecid also inhibits OAT1 and OAT3, leading to OAT1/3-dependent drug-drug interactions that limits its use. The URAT1 inhibitor lesinurad has detectable interactions with OAT1 and OAT3 in vitro, but in contrast to probenecid has no clinically relevant OAT1/3-dependent drug-drug interactions [42,43]. Because of the relatedness to URAT1, all URAT1 inhibitors under evaluation for treatment of hyperuricemia associated with gout should be evaluated against OAT1 and OAT3.…”

Revisiting Gout With New Treatment Strategy: Lesinurad.

“…[25] Effective and convenient treatment options are clearly needed for those patients who do not achieve sUA targets on available ULTs and require Clinical trials in healthy volunteers indicate that a single dose of lesinurad increases fractional excretion of uric acid (FEUA), in an exposure-dependent manner and that lesinurad treatment significantly reduces serum uric acid (sUA). [27] A similar study by Miner et al [28] defined the mechanism of action by evaluating sUA levels, fractional excretion of uric acid (FEUA), lesinurad plasma levels and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. After 6 hours, a single 200-mg dose of lesinurad elevated FEUA 3.6-fold (p<0.001) and reduced sUA levels by 33 % (p<0.001).…”

The problems associated with the treatment of chronic hyperuricaemia in Serbia

“…Lesinurad predstavlja najnoviji odobreni vid adjuvantne terapije hiperurikemije koji svoje delovanje ostvaruje kroz blokadu dva transportera koji omogućavaju reapsorpciju mokraćne kiseline-URAT1 I OAT4 transportera [58][59]. Lesinurad je odobren za primenu isključivo kao adjuvantna antihiperurikemijska terapija inhibitorima ksantin-oksidaze kod onih pacijenata kod kojih monoterapija alopurinolom ili febuksostatom nije dovela do dostizanja ciljnih koncentracija serumskih urata, pa se lesinurad nikako ne sme koristiti kao monoterapija.…”