lesinurad (Discontinued)

1-10%

Headache (5.3%)

Influenza (5.1%)

GERD (2.7%)

Renal failure (1.2%)

Serum creatinine

• Increased creatinine (4.3%)
• Elevation 1.5 to <2 x baseline (3.9%)
• Elevation ≥2 x baseline (1.8%)
• Nearly 90% resolved by end of study

<1%

Nephrolithiasis

Contraindications

Severe renal impairment (estimated CrCl <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis

Tumor lysis syndrome or Lesch-Nyhan syndrome

Cautions

Adverse effects related to renal function have occurred after initiating lesinurad; incidence was higher with doses exceeding 200 mg/day, with the highest incidence occurring with monotherapy use; monitor renal function at initiation and during therapy, particularly in patients with estimated CrCl <60 mL/min, and evaluate for signs and symptoms of acute uric acid nephropathy

Major adverse cardiovascular events were observed during clinical trials (defined as cardiovascular deaths, nonfatal myocardial infarctions, or nonfatal strokes); a causal relationship has not been established

Drug interaction overview

• Lesinurad is a CYP2C9 substrate and its exposure is increased when coadministered with CYP2C9 inhibitors and in CYP2C9 poor metabolizers, while its exposure is decreased when coadministered with CYP2C9 inducers
• Lesinurad is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme for induction or inhibition; caution with sensitive CYP3A substrates
• In vitro studies suggest that lesinurad is not an inhibitor of epoxide hydrolase; however, inhibitors of epoxide hydrolase (ie, valproic acid) may interfere with metabolism of lesinurad; should not be administered with epoxide hydrolase inhibitors
• Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when lesinurad is coadministered; use additional methods of nonhormonal contraception
• Doses of aspirin >325 mg/day may decrease lesinurad efficacy
• 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
• 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

Pregnancy

There are no available human data on use in pregnant women to inform a drug-associated risk

Animal data

• No teratogenicity or effects on fetal development were observed in embryo-fetal development studies with oral administration of lesinurad to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to approximately 45 and 10 times, respectively, the exposure at the maximum recommended human dose (MRHD)
• No adverse developmental effects were observed in a prenatal and postnatal development study with administration of lesinurad to pregnant rats from organogenesis through lactation at a dose approximately 5 times the MRHD

Lactation

Unknown if distributed in human breast milk It is present in the milk of rats

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Selective uric acid reabsorption inhibitor (SURI); it acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid

It also inhibits organic anion transporter 4 (OAT4), a uric acid transporter associated with diuretic-induced hyperuricemia

Absorption

Absolute bioavailability: ~100%

Peak plasma time: 1-4 hr

Peak plasma concentration: 6 mcg/mL

AUC: 30 mcg·hr/mL

Distribution

Protein bound: >98% (mainly albumin)

Vd: 20 L

Metabolism

Undergoes oxidative metabolism mainly via CYP2C9

Elimination

Half-life: ~5 hr

Total body clearance: 6 L/hr

Excretion: 63% urine (30% of this as unchanged drug); 32% feces

Pharmacogenomics

Lesinurad is a CYP2C9 substrate

Increased systemic exposure may be observed with slow metabolizers of CYP2C9

Exposure was ~1.8-fold higher in CYP2C9 poor metabolizers (ie, subjects with CYP2C9 *2/*2 [N=1], and *3/*3 [N=1] genotype) compared with CYP2C9 extensive metabolizers (ie, CYP2C9 *1/*1 [N=41] genotype)

Oral Administration

Coadminister with a xanthine oxidase inhibitor

Not recommended for patients taking allopurinol <300 mg/day (or <200 mg/day if estimated CrCl <60 mL/min)

Take at the same time as the morning dose of xanthine oxidase inhibitor

If treatment with the xanthine oxidase inhibitor is interrupted, lesinurad should also be interrupted

Patients should be instructed to stay well hydrated (eg, 2 liters [68 oz] of liquid per day)

Failure to follow these instructions may increase the risk of renal events

Storage

Store at 20-25°C (68-77°F); excursions permitted from 15-30°C (59-86°F)