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Lesinurad response

MedGen UID:
916027
Concept ID:
CN248784
Sign or Symptom
Synonym: Zurampic response
Drug:
lesinurad
MedGen UID:
844293
Concept ID:
C3886073
Organic Chemical
 
Gene (location): CYP2C9 (10q23.33)

Definition

Lesinurad (brand name Zurampic) is a urate transport inhibitor used in the treatment of gout. Gout is one of the most common types of inflammatory arthritis, affecting approximately 3% of adults worldwide. It is caused by the accumulation of urate crystals in joints. The long-term management of gout includes reducing risk factors (e.g., obesity, alcohol use, diuretic use, poor renal function), and medication to lower uric acid levels. Lesinurad reduces the high level of uric acid (hyperuricemia) associated with gout. Lesinurad should only be used in combination with a xanthine oxidase inhibitor (e.g., allopurinol, febuxostat) –– the risk of acute renal failure is increased if lesinurad is used alone. The addition of lesinurad to gout treatment is reserved for patients who have failed to achieve their target uric acid level despite being treated with a xanthine oxidase inhibitor. Xanthine oxidase inhibitors reduce uric acid by inhibiting its production, whereas lesinurad reduces uric acid by blocking its reabsorption in the kidney. Lesinurad is primarily metabolized by CYP2C9 to several inactive metabolites. Individuals who lack CYP2C9 activity ("CYP2C9 poor metabolizers") have an increased exposure to lesinurad, and an increased risk of side effects. Adverse reactions of lesinurad therapy include kidney stones and other kidney problems. Lesinurad is also associated with an increased risk of cardiovascular events. The FDA-approved drug label for lesinurad states that lesinurad should be used with caution in CYP2C9 poor metabolizers, but does not provide specific dose adjustments in this group. The standard dose of lesinurad is 200 mg daily. Lesinurad is contraindicated in patients with severe impairment of kidney function (e.g., kidney transplant and hemodialysis patients) as well as individuals with tumor lysis syndrome or Lesch-Nyhan syndrome. [from Medical Genetics Summaries]

Professional guidelines

PubMed

Haber SL, Fente G, Fenton SN, Walker EP, Weaver BM, Cano AJ, Vu K
Ann Pharmacother 2018 Jul;52(7):690-696. Epub 2018 Feb 26 doi: 10.1177/1060028018762103. PMID: 29482353
Schlee S, Bollheimer LC, Bertsch T, Sieber CC, Härle P
Z Gerontol Geriatr 2018 Aug;51(6):703-710. Epub 2017 Feb 28 doi: 10.1007/s00391-017-1199-1. PMID: 28246893
Jones G, Panova E, Day R
Drug Des Devel Ther 2017;11:3077-3081. Epub 2017 Oct 24 doi: 10.2147/DDDT.S97959. PMID: 29123379Free PMC Article

Curated

DailyMed Drug Label, ZURAMPIC, 2018

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted 1 information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2018 Statement from the US Food and Drug Administration (FDA)

Lesinurad exposure is increased when lesinurad is co-administered with inhibitors of CYP2C9, and in CYP2C9 poor metabolizers. Lesinurad should be used with caution in patients taking moderate inhibitors of CYP2C9 (e.g., fluconazole, amiodarone), and in CYP2C9 poor metabolizers.

Lesinurad exposure is decreased when lesinurad is co-administered with moderate inducers of CYP2C9 (e.g., rifampin, carbamazepine), which may decrease the therapeutic effect of lesinurad.

[…]

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.

Please review the complete therapeutic recommendations that are located here: (1).

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labelled all formulations containing the generic drug.

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