Chemical formula: C₁₇H₁₄BrN₃O₂S Molecular mass: 404.28 g/mol PubChem compound: 53465279
Lesinurad is a selective uric acid reabsorption inhibitor that inhibits uric acid transporter URAT1. URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen. By inhibiting URAT1, lesinurad increases uric acid excretion and thereby lowers serum uric acid (sUA). Lesinurad also inhibits OAT4, a uric acid transporter involved in diuretic-induced hyperuricaemia.
Lesinurad, when combined with a xanthine oxidase inhibitor, increases uric acid excretion and decreases uric acid production resulting in greater sUA lowering. Lesinurad should only be used in combination with a xanthine oxidase inhibitor because combination use reduces the amount of uric acid available for excretion and decreases the risk of renal-related events.
In healthy subjects, lesinurad 200 mg lowered sUA levels and increased renal clearance and fractional excretion of uric acid. Mean sUA reductions following lesinurad 200 mg administration alone were approximately 46% and 26% at 6 hours and 24 hours post-dose, respectively. When lesinurad 200 mg was added to a xanthine oxidase inhibitor (i.e. febuxostat), additional 25% and 19% of sUA reductions were observed at 6 hours and 24 hours post-dose, respectively.
Lesinurad at doses up to 1,600 mg did not demonstrate an effect on ECG parameters (including QTc interval) in healthy subjects.
The absolute bioavailability of lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single oral dose of lesinurad in either the fed or fasted state, maximum plasma concentrations (Cmax) were attained within 1 to 4 hours. Cmax and AUC exposures of lesinurad increased proportionally with single doses of lesinurad from 5 to 1,200 mg. In the fed state, after a single dose of lesinurad 200 mg, geometric mean lesinurad Cmax and AUC were 6 μg/mL and 29 μg/hr/mL, respectively. There was no apparent influence of the fat content in the meal on the pharmacokinetics of lesinurad. In clinical trials, lesinurad was administered with food, because the serum uric acid lowering was improved under fed conditions.
Lesinurad is administered as a 50:50 mixture of lesinurad atropisomers. The ratio of atropisomer 1 to atropisomer 2 AUC was 44:56 because atropisomer 1 undergoes more extensive metabolism than atropisomer 2, causing atropisomer 1 to have lower plasma exposure than atropisomer 2.
Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The mean steady state volume of distribution of lesinurad was approximately 20 L following intravenous dosing. Mean plasma-to-blood ratios of lesinurad AUC and Cmax were approximately 1.8, indicating that radioactivity was largely contained in the plasma space and did not penetrate or partition extensively into red blood cells.
Lesinurad undergoes oxidative metabolism mainly via cytochrome P450 (CYP) 2C9 to intermediate metabolite M3c (not detected in vivo) and is subsequently metabolised by mEH to metabolite M4; there is minimal contribution from CYP1A1, CYP2C19, and CYP3A to the metabolism of lesinurad. Atropisomer 1 is extensively metabolised by CYP2C9 whereas atropisomer 2 is minimally metabolised by both CYP2C9 and CYP3A4. It is unclear if metabolite plasma exposures are minimal. Metabolites are not known to contribute to the uric acid lowering effects of lesinurad.
Renal clearance is 25.6 mL/min (CV=56%). Lesinurad is highly protein bound and renal clearance is high (as compared to typical human glomerular filtration rate), indicating that active secretion plays an important role in the renal excretion of lesinurad. Within 7 days following single dosing of radiolabelled lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in faeces. Most of the radioactivity recovered in urine (>60% of dose) occurred in the first 24 hours. Unchanged lesinurad in urine accounted for approximately 30% of the dose. The elimination half-life (t½) of lesinurad was approximately 5 hours following a single dose. Lesinurad does not accumulate following multiple doses.
Following multiple once daily dosing of lesinurad, there was no evidence of time dependent changes in pharmacokinetic properties and dose proportionality was preserved.
Lesinurad is mainly metabolised by CYP2C9 and mEH, and to a lesser extent by CYP1A1, CYP2C19 and CYP3A. In vitro, lesinurad is an inhibitor of CYP2C8, but not of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and mEH. In addition, lesinurad is an in vitro inducer of CYP2B6 and CYP3A via CAR/PXR. In vivo, lesinurad is neither an inhibitor nor an inducer of CYP2C9 and 2C8, but a mild to moderate inducer of CYP3A. CYP2B6 has not been studied in vivo.
Lesinurad is a substrate of OATP1B1, OAT1, OAT3 and OCT1. In vitro, lesinurad is an inhibitor of OATP1B1, OAT1, OAT3, OAT4 and OCT1 at clinically relevant plasma concentrations. However, the in vivo activity of OATP1B1, OAT1, OAT3 and OCT1 was not affected by lesinurad. Lesinurad is not an in vitro inhibitor of P-glycoprotein, BCRP, OATP1B3, MRP2, MRP4, OCT2, MATE1 and MATE2-K.
The population pharmacokinetic analysis of clinical data in gout patients treated for up to 12 months estimated increases in lesinurad exposure of approximately 12%, 31% and 65% in patients with mild, moderate, and severe renal impairment, respectively, compared with patients with normal renal function.
Following administration of a single dose of lesinurad to individuals with renal impairment compared to those with normal renal function lesinurad Cmax and AUC, respectively, were 36% and 30% higher (200 mg) in patients with mild renal impairment (eCrCL 60 to 89 mL/min), 20% and 73% higher (200 mg) and 3% and 50% higher (400 mg) in patients with moderate renal impairment (eCrCL 30 to 59 mL/min), and 13% higher and 113% higher (400 mg) in patients with severe renal impairment (eCrCL <30 mL/min).
Following administration of a single dose of lesinurad at 400 mg in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, lesinurad Cmax was comparable and lesinurad AUC was 7% and 33% higher, respectively, compared to individuals with normal hepatic function. There is no clinical experience in patients with severe (Child-Pugh class C) hepatic impairment.
Approximately half of an oral dose of lesinurad is cleared via CYP2C9 metabolism. The effect of CYP2C9 genotype on the pharmacokinetics of lesinurad was studied in 8 healthy subjects and 59 patients with gout following daily dosing of lesinurad ranging from 200 mg to 600 mg in the absence or presence of a xanthine oxidase inhibitor. At the 400 mg dose, when compared with extensive CYP2C9 metabolisers (CYP2C9 *1/*1 [N=41]), increased lesinurad exposures were observed in intermediate CYP2C9 metabolisers (CYP2C9 *1/*3 [N=4], approximately 22% increase in AUC) and in poor CYP2C9 metabolisers (CYP2C9 *3/*3 [N=1], approximately 111% increase in AUC) accompanied with higher lesinurad renal excretion. However, individual values were well within the range observed in the extensive metaboliser subjects.
Patients who are known or suspected to be CYP2C9 poor metabolisers based on previous history or experience with other CYP2C9 substrates should use lesinurad with caution.
Based on population pharmacokinetic analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of lesinurad. Based on pharmacokinetic modelling simulations, patients with moderate renal impairment and reduced CYP2C9 activity (co-administration of a CYP2C9 inhibitor or a CYP2C9 poor metabolizer) are predicted to have an increase in AUC of approximately 200% in comparison to normal renal function and unimpaired CYP2C9 activity.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
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