By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first selective uric acid reabsorption inhibitor for the treatment of hyperuricemia associated with gout, in combination with a xanthine oxidase inhibitor (XOI). This is the first uricosuric agent to be approved since probenecid. Lesinurad is marketed by AstraZeneca as Zurampic.
INDICATION
Lesinurad is indicated in combination with a XOI (allopurinol or febuxostat) for the treatment of hyperuricemia associated with gout in patients who have not achieved target uric acid levels. The drug should not be initiated in patients with estimated CrCl < 45 mL/min.
DOSAGE
The recommended and maximum dose is 200 mg taken once daily in the morning with food and water at the same time as the XOI.1 Gout flare prophylaxis is recommended. Lesinurad is available as 200 mg tablets.
POTENTIAL ADVANTAGES
Lesinurad is a drug with a different mechanism of action to augment the action of a XOI, resulting in additional reduction of serum uric acid levels.
POTENTIAL DISADVANTAGES
Lesinurad has been associated with serum creatinine elevation. The drug carries a boxed warning regarding the risk of acute renal failure if used in higher than recommended doses or without a XOI. Renal function should be assessed prior to treatment initiation.1 Major cardiovascular events (death, nonfatal myocardial infarction, or stroke) were numerically higher with lesinurad compared to placebo. Co-administration with a CYP2C9 inhibitor increases the exposure of lesinurad.1 Levels are reduced if co-administered with a CYP2C9 inducer. Co-administration with an epoxide hydrolase inhibitor (e.g., valproic acid) is not recommended. Doses of aspirin > 325 mg/day may reduce the effectiveness of lesinurad.
COMMENTS
Lesinurad reduces serum uric acid levels by inhibiting two transporters, uric acid transporter and organic anion transporter.1 Its efficacy was evaluated in three randomized, 12-month, double-blind, placebo-controlled studies in 1537 adults with gout and hyperuricemia. In two studies, lesinurad was added to allopurinol (300 mg/day or 200 mg with renal impairment) in subjects with inadequate lowering of uric acid, and the third to febuxostat in subjects with tophaceous gout. The primary endpoint was the proportion of subjects achieving serum uric acid levels < 6 mg/dL or < 5 mg/dL. In the first two studies, the combination of lesinurad (200 mg/day) and allopurinol, 54% and 55% achieved target (< 6 mg/dL) compared to 28% and 23%, respectively in patients on placebo and allopurinol, at 6 months. The response was maintained at 12 months. In the third study, the combination of lesinurad (200 mg) and febuxostat (80 mg/day) achieved uric acid target of < 5 mg/dL in 57% compared to 47% with febuxostat plus placebo. This did not achieve statistical significance. In all three studies, the rate of gout flares and tophus outcome were not statistically different; however, all subjects received prophylaxis for gout flares with colchicine or nonsteroidal anti-inflammatory drugs for the first 5 months of treatment. The efficacy of lesinurad appears to be reduced in subjects with decreased renal function.1 Most frequently reported adverse events (compared to placebo) were headache (5.3% vs 4.1%), influenza (5.1% vs 2.7%), and gastroesophageal reflux disease (2.7% vs 0.8%). There are no published comparisons between lesinurad and probenecid.
CLINICAL IMPLICATIONS
Gout is a common rheumatic disease in adults, with symptoms generally manifested due to hyperuricemia. The goal for pharmacotherapy is to reduce urine acid levels. The first line of therapy is an XOI (allopurinol or febuxostat) with a serum urate target of < 6 mg/dL and, in some cases, < 5 mg/dL. If this is inadequate, the American College or Rheumatology recommends adding an uricosuric agent such as probenecid, fenofibratre, or losartan.2 Lesinurad provides another option for the management of hyperuricemia inadequately controlled on a XOI, particularly allopurinol. The future role remains to be determined. The FDA is requiring postmarketing studies to evaluate renal and cardiovascular safety. The cost and availability are not known at the time of this review.
REFERENCES
- Zurampic Prescribing Information. AstraZeneca. December 2015.
- Khanna D, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:1431-1446.
Lesinurad is a drug with a different mechanism of action to augment the action of a xanthine oxidase inhibitor, resulting in additional reduction of serum uric acid levels.
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