Mechanism Of Action
DUZALLO combines two medications with complementary mechanisms of action for treatment of hyperuricemia associated with gout: lesinurad, a uric acid reabsorption inhibitor, and allopurinol, a xanthine oxidase inhibitor. DUZALLO lowers serum uric acid levels by increasing excretion and inhibiting production of uric acid.
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 μM, 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.
Allopurinol acts on purine catabolism, without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. Allopurinol is a structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in humans. Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.
Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol and oxypurinol. This reutilization does not disrupt normal nucleic acid anabolism because feedback inhibition is an integral part of purine biosynthesis. As a result of xanthine oxidase inhibition, the serum concentration of hypoxanthine plus xanthine in patients receiving allopurinol for treatment of hyperuricemia is usually in the range of 0.3 to 0.4 mg/dL compared to a normal level of approximately 0.15 mg/dL. A maximum of 0.9 mg/dL of these oxypurines has been reported when the serum urate was lowered to less than 2 mg/dL by high doses of allopurinol. These values are far below the saturation levels at which point their precipitation would be expected to occur (above 7 mg/dL).
Effects On Serum Uric Acid And Urinary Excretion Of Uric Acid
In gout patients, lesinurad lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid. Following single and multiple oral doses of lesinurad to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed.
Allopurinol reduces both the serum and urinary uric acid levels by inhibiting the formation of uric acid.
Effect On Cardiac Repolarization
The effect of lesinurad on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and gout patients. Lesinurad at doses up to 1600 mg did not demonstrate an effect on the QTc interval.
The effect of allopurinol on cardiac repolarization has not been evaluated.
After the administration of DUZALLO with a high-fat breakfast in healthy subjects, the exposure (AUC) for lesinurad and allopurinol were comparable to the fasted state. Compared to the fasted state, the fed state resulted in 46% and 18% reductions and 2.5 hours and 1.75 hours delays, in the peak (Cmax) concentrations of lesinurad and allopurinol, respectively. This effect of food is not considered to be clinically meaningful. Oxypurinol Cmax and AUC were similar in the fed and fasted states.
The absolute bioavailability of lesinurad as monotherapy is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single dose of a lesinurad tablet in either fed or fasted state, Cmax was attained within 1 to 4 hours. Cmax and AUC exposures of lesinurad increased proportionally with single doses of lesinurad 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 Cmax by up to 18% but does not alter AUC as compared with fasted state. In clinical trials, lesinurad was administered with food.
Allopurinol is approximately 90% absorbed from the gastrointestinal tract. Peak plasma levels generally occur at
1.5 hours and 4.5 hours for allopurinol and oxypurinol, respectively. After a single oral dose of 300 mg allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxypurinol are produced.
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 lesinurad.
The elimination half-life (t½) of lesinurad is approximately 5 hours. Lesinurad does not accumulate following multiple doses. The total body clearance is approximately 6 L/hr.
Because of its rapid oxidation to oxypurinol and a renal clearance rate approximately that of glomerular filtration rate, allopurinol has a plasma half-life of about 1 to 2 hours. Oxypurinol, however, has a longer plasma elimination half-life (approximately 26 hours) and therefore effective xanthine oxidase inhibition is maintained over a 24-hour period with single daily doses of allopurinol. Whereas allopurinol is cleared essentially by glomerular filtration, oxypurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid.
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 lesinurad. 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, lesinurad 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].
Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.
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.
Approximately 20% of the ingested allopurinol is excreted in the feces. The remainder is primarily metabolized to oxypurinol.
A dedicated renal impairment study was not conducted with DUZALLO.
Two dedicated studies were performed to assess pharmacokinetics (PK) of lesinurad 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 PK of lesinurad 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 PK of lesinurad 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.
Allopurinol and its metabolites are primarily eliminated by the kidney. Impairment of renal function may lead to retention of the drug and its metabolites with consequent prolongation of action. Patients with reduced renal function require lower doses of allopurinol than those with normal renal function.
A dedicated hepatic impairment study was not conducted with DUZALLO.
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.
No information is available in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].
Effect Of Age, Gender, Race And Ethnicity On Pharmacokinetics
Based on the population PK analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the PK of lesinurad [see Use In Specific Populations].
No information is available for age, gender, race, or ethnicity effects on the PK of allopurinol.
Studies characterizing the PK of lesinurad in pediatric patients have not been conducted.
No data on the PK of allopurinol in pediatric patients are available.
Pharmacokinetic drug interaction studies with DUZALLO have not been performed; however, such studies have been conducted with the individual components lesinurad and allopurinol.
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).
Effects of Other Drugs on Lesinurad
Figure 1 shows the effect of co-administered drugs on the PK 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 Pglycoprotein.
Figure 2 shows the effect of lesinurad on co-administered drugs.
Figure 2: Effect of Lesinurad on the Pharmacokinetics of Coadministered Drugs
Effect of Allopurinol on Mercaptopurine
Allopurinol inhibits the enzymatic oxidation of mercaptopurine, the sulfur-containing analogue of hypoxanthine, to 6-thiouric acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates mercaptopurine. Hence, the inhibition of such oxidation by allopurinol may result in as much as a 75% reduction in the therapeutic dose requirement of mercaptopurine when the two compounds are given together.
Lesinurad in combination with allopurinol has been studied in hyperuricemic gout patients who have not achieved target serum uric acid levels with allopurinol alone.
There have been no phase 3 clinical trials with DUZALLO. Bioequivalence of DUZALLO to co-administered lesinurad and allopurinol was demonstrated, and efficacy of the combination of allopurinol and lesinurad has been demonstrated in two phase 3 studies (Study 1 and 2).
Lesinurad Add-On To Allopurinol In Inadequate Responders
Both studies were 12-month multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout. Patients received prophylaxis for gout flares with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of study treatment. Lesinurad 200 mg and 400 mg
once daily in combination with allopurinol were studied. Lesinurad 200 mg is the only recommended lesinurad dose, and is the dose combined with allopurinol in DUZALLO.
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), 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 were randomized 1:1:1 to receive lesinurad 200 mg, lesinurad 400 mg, or placebo once daily; all were to continue on their stable allopurinol dose. The majority of patients in these studies, received daily allopurinol doses of 200 mg or 300 mg, corresponding to the allopurinol doses contained in DUZALLO. The average dose of allopurinol in the studies was 310 mg (range: 200900 mg).
As shown in Table 5, lesinurad 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 Lesinurad in Combination With Allopurinol
||Patients Achieving Serum Uric Acid Target
||Difference of Proportion
|Placebo + Allopurinol
||Lesinurad 200 mg + Allopurinol
|Study 1 (N=402*)
( 0.17, 0.36)
|Study 2 (N=410*)
|* Number of patients in the 2 treatment groups shown. Number of patients in all 3 treatment groups N=603 for Study 1 and N=610 for Study 2.
The estimated effect of lesinurad 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 lesinurad 200 mg in combination with allopurinol at the Month 1 visit and was maintained throughout the 12-month studies.
Figure 3: Mean Serum Uric Acid Levels Over Time in Pooled Clinical Studies With Lesinurad in Combination With Allopurinol (Study 1 and Study 2)
In Study 1 and Study 2, the rates of gout flare requiring treatment from the end of Month 6 to the end of Month 12 were not statistically different between lesinurad 200 mg in combination with allopurinol compared with allopurinol alone.
Use In Patients With Renal Impairment
The estimated differences between lesinurad 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 studies. However, there were limited data in patients with eCLcr less than 45 mL/min and there was a trend toward decreasing magnitude of effect with decreasing renal function. Based on integrated data from Study 1 and Study 2, the estimated difference between lesinurad 200 mg in combination with allopurinol and allopurinol alone in the proportion achieving serum uric acid < 6.0 mg/dL at Month 6 was 10% (95% CI: -17, 37) in those with eCLcr less than 45 mL/min 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.