micro;g•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.
Absorption
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.
Distribution
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.
Elimination
The elimination half-life (t½) of lesinurad was approximately 5 hours. ZURAMPIC does not accumulate following multiple doses. The total body clearance is approximately 6 L/hr.
Metabolism
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 (7.1)].
Excretion
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.
Special Populations
Renal Impairment
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 eva luating 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= |
