Mechanism Of Action
Lesinurad reduces serum uric acid levels by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney. Lesinurad inhibited the function of two apical transporters responsible for uric acid reabsorption, uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), with IC50 values of 7.3 and 3.7 ÃÂ¼M, respectively. URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen. OAT4 is a uric acid transporter associated with diuretic-induced hyperuricemia. Lesinurad does not interact with the uric acid reabsorption transporter SLC2A9 (Glut9), located on the basolateral membrane of the proximal tubule cell.
Effects On Serum Uric Acid And Urinary Excretion Of Uric Acid
In gout patients, ZURAMPIC lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid. Following single and multiple oral doses of ZURAMPIC to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed.
Effect On Cardiac Repolarization
The effect of ZURAMPIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and gout patients. ZURAMPIC at doses up to 1600 mg did not demonstrate an effect on the QTc interval.
Following oral administration of ZURAMPIC 200 mg in healthy subjects, the mean (% CV) Cmax and AUC for lesinurad were 6 ÃÂ¼g/mL (31%) and 30 ÃÂ¼g•hr/mL (44%), respectively. Cmax and AUC exposures of lesinurad increased proportionally with single doses of ZURAMPIC from 5 to 1200 mg. Following multiple once daily dosing of ZURAMPIC, there was no evidence of time dependent changes in pharmacokinetics and dose proportionality was preserved.
The absolute bioavailability of lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single dose of a ZURAMPIC tablet in either 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 ZURAMPIC from 5 to 1200 mg.
Administration with a high-fat meal (800 to 1000 calories with 50% of calories being derived from fat content) decreases lesinurad Cmax by up to 18% but does not alter AUC as compared with fasted state. In clinical trials, ZURAMPIC was administered with food.
Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin. Plasma protein binding of lesinurad 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 of ZURAMPIC.
The elimination half-life (tÃ½) of lesinurad was approximately 5 hours. ZURAMPIC does not accumulate following multiple doses. The total body clearance is approximately 6 L/hr.
Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme. Plasma exposure of metabolites is minimal (<10% of unchanged lesinurad). Metabolites are not known to contribute to the uric acid lowering effects of ZURAMPIC. A transient oxide metabolite is rapidly eliminated by microsomal epoxide hydrolase in the liver and not detected in plasma.
Patients who are CYP2C9 poor metabolizers are deficient in CYP2C9 enzyme activity. A cross-study pharmacogenomic analysis assessed the association between CYP2C9 polymorphism and lesinurad exposure in patients receiving single or multiple doses of lesinurad at 200 mg, 400 mg or 600 mg. At the 400 mg dose, ZURAMPIC exposure was approximately 1.8-fold higher in CYP2C9 poor metabolizers (i.e., subjects with CYP2C9 *2/*2 [N=1], and *3/*3 [N=1] genotype) compared to CYP2C9 extensive metabolizers (i.e., CYP2C9 *1/*1 [N=41] genotype). Use with caution in CYP2C9 poor metabolizers, and in patients taking moderate inhibitors of CYP2C9 [see DRUG INTERACTIONS].
Within 7 days following single dosing of radiolabeled lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces. 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.
Two dedicated studies were performed to assess PK in renal impairment (classified using the Cockcroft-Gault formula) subjects. In both studies, Cmax was comparable in renal impairment subjects compared to healthy subjects.
Study 1 was a single-dose, open-label study evaluating the pharmacokinetics of ZURAMPIC 200 mg in subjects with mild (eCLcr 60 to less than 90 mL/min)
and moderate renal impairment (eCLcr 30 to less than 60 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6; eCLcr greater than or equal to 90 mL/min), plasma AUC of lesinurad was increased by approximately 30% and 73% in subjects with mild (N=8) and moderate (N=10) renal impairment, respectively.
Study 2 was a single-dose, open-label study evaluating the pharmacokinetics of ZURAMPIC 400 mg in subjects with moderate and severe renal impairment (eCLcr less than 30 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6), plasma AUC of lesinurad was increased by approximately 50% and 113% in subjects with moderate (N=6) and severe (N=6) renal impairment, respectively.
Following administration of a single dose of ZURAMPIC 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.
Effect Of Age, Gender, Race And Ethnicity On Pharmacokinetics
Based on the population pharmacokinetic analysis, age, gender, race and ethnicity
do not have a clinically meaningful effect on the pharmacokinetics of lesinurad [see Use In Specific Populations].
Studies characterizing the pharmacokinetics of lesinurad in pediatric patients have not been conducted.
Effects Of Other Drugs On Lesinurad
Based on in vitro data, lesinurad is a substrate for CYP2C9, OAT1 and OAT3; however, no clinical studies have been conducted with OAT1 and OAT3 inhibitors (eg, probenecid).
Figure 1 shows the effect of co-administered drugs on the pharmacokinetics of lesinurad.
Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Lesinurad
Effects Of Lesinurad On Other Drugs
Lesinurad is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme for induction (CYP1A2, CYP2C8, CYP2C9, CYP2B6, or CYP2C19) or inhibition (CYP1A2, CYP2B6, CYP2D6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4).
Based on in vitro studies, lesinurad is an inhibitor of OATP1B1, OCT1, OAT1, and OAT3; however, lesinurad is not an in vivo inhibitor of these transporters. In vivo drug interaction studies indicate that lesinurad does not decrease the renal clearance of furosemide (substrate of OAT1/3), or affect the exposure of atorvastatin (substrate of OATP1B1) or metformin (substrate of OCT1). Based on in vitro studies, lesinurad has no relevant effect on P-glycoprotein.
Figure 2 shows the effect of lesinurad on co-administered drugs.
Figure 2: Effect of Lesinurad on the Pharmacokinetics of Co-administered Drugs
Overview Of Clinical Studies Of ZURAMPIC
The efficacy of ZURAMPIC 200 mg and 400 mg once daily was studied in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout in combination with a xanthine oxidase inhibitor, allopurinol or febuxostat. All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of ZURAMPIC treatment.
Although other doses have been studied, the recommended dose of ZURAMPIC is 200 mg once daily in combination with a xanthine oxidase inhibitor.
Add-On To Allopurinol In Inadequate Responders
Study 1 and Study 2 enrolled patients with gout who were on a stable dose of allopurinol of at least 300 mg (or 200 mg for moderate renal impairment) that had a serum uric acid > 6.5 mg/dL and reported at least 2 gout flares in the prior 12 months. Mean years since gout diagnosis were 12 years. More than half of the patients (61%) had mild or moderate renal impairment and 19% of the patients had tophi. Patients continued their allopurinol dose and were randomized 1:1:1 to receive ZURAMPIC 200 mg, ZURAMPIC 400 mg, or placebo once daily. The average dose of allopurinol in the studies was 310 mg (range: 200-900 mg).
As shown in Table 5, ZURAMPIC 200 mg in combination with allopurinol was superior to allopurinol alone in lowering serum uric acid to less than 6 mg/dL at Month 6.
Table 5: Proportion of Patients Achieving Target Serum Uric Acid Levels
(< 6 mg/dL) in Two Studies of ZURAMPIC in Combination with Allopurinol
||Patients Achieving Serum
Uric Acid Target
||Difference of Proportion
200 mg vs
( 0.17, 0.36)
The estimated effect of ZURAMPIC 200 mg on serum uric acid in the subgroup of patients taking thiazide diuretics at baseline was similar to the estimated effect in the overall population. The estimated effect was also similar in the subgroup of patients taking low dose aspirin at baseline.
As shown in Figure 3, reduction in average serum uric acid levels to < 6 mg/dL was noted for ZURAMPIC 200 mg in combination with allopurinol at the Month 1 visit and was maintained throughout the 12-month study.
Figure 3: Mean Serum Uric Acid Levels Over Time in Pooled Clinical Studies with ZURAMPIC in Combination with Allopurinol (Study 1 and Study 2)
Combination With Febuxostat In Tophaceous Gout
Study 3 enrolled gout patients with measurable tophi. Patients received febuxostat 80 mg once daily for 3 weeks and then were randomized 1:1:1 to once daily doses of ZURAMPIC 200 mg, ZURAMPIC 400 mg, or placebo in combination with febuxostat. A total of 66% of patients had mild or moderate renal impairment. Fifty percent of patients did not reach target serum uric acid < 5.0 mg/dL at Baseline after 3 weeks of febuxostat treatment.
As shown in Table 6, there was not statistical evidence of a difference in the proportion of patients treated with ZURAMPIC 200 mg in combination with febuxostat achieving a serum uric acid < 5 mg/dL by Month 6, compared with patients receiving febuxostat alone. However, the average decrease in serum uric acid with ZURAMPIC 200 mg in Study 3 was similar to that seen in Study 1 and Study 2 (see Figure 3 and Figure 4).
Table 6: Proportion of Patients Achieving Target Serum Uric Acid Levels
(< 5 mg/dL) in a Study with ZURAMPIC in Combination with Febuxostat in Tophaceous Gout
||Patients Achieving Serum Uric Acid Target
||Difference of Proportion
+ Febuxostat 80 mg
||ZURAMPIC 200 mg
+ Febuxostat 80 mg
||ZURAMPIC 200 mg vs
As shown in Figure 4, reduction in average serum uric acid levels to < 5 mg/dL was noted for ZURAMPIC 200 mg in combination with febuxostat at the Month 1 visit and was maintained throughout the 12-month study.
Figure 4: Mean Serum Uric Acid Levels Over Time in a Study with ZURAMPIC in Combination with Febuxostat in Tophaceous Gout (Study 3)
Gout Flares And Tophus Outcomes
In each of the three pivotal studies of ZURAMPIC in combination with a xanthine oxidase inhibitor, the rates of gout flare requiring treatment from the end of Month 6 to the end of Month 12 were not statistically different between ZURAMPIC 200 mg in combination with allopurinol or febuxostat compared with allopurinol or febuxostat alone. In Study 3, the proportion of patients who experienced a complete resolution of ≥ 1 target tophus was not statistically different between ZURAMPIC 200 mg in combination with febuxostat compared with febuxostat alone.
Use In Patients With Renal Impairment
The estimated differences between ZURAMPIC and placebo in the proportions of patients achieving target serum uric levels in the renal impairment subgroups were largely consistent with the results in the overall population in the three studies. However, there were limited data in patients with eCLcr less than 45 mL/min and there was a trend toward decreasing magnitudes of effect with decreasing renal function: in patients with eCLcr less than 45 mL/min, the estimated difference between ZURAMPIC 200 mg and placebo in the proportion achieving serum uric acid < 6.0 mg/dL at Month 6 was 10% (95% CI: -17, 37), as compared with 27% (95% CI: 9, 45) in the 45 to less than 60 mL/min subgroup and 30% (95% CI: 23, 37) in the 60 mL/min or greater subgroup, based on integrated data from Study 1 and Study 2.