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 eva luating the pharmacokinetics of ZURAMPIC 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.
Hepatic Impairment
Following administration of a single dose of ZURAMPIC 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.
Effect of Age, Gender, Race and Ethnicity on Pharmacokinetics
Based on the population pharmacokinetic analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of lesinurad [see USE IN SPECIFIC POPULATIONS (8.5)].
Pediatric Use
Studies characterizing the pharmacokinetics of lesinurad in pediatric patients have not been conducted.
Drug-Drug Interactions
Effects of Other Drugs on Lesinurad
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).
Figure 1 shows the effect of co-administered drugs on the pharmacokinetics of lesinurad.
Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Lesinurad
Figure 1
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 P-glycoprotein.
Figure 2 shows the effect of lesinurad on co-administered drugs.
Figure 2: Effect of Lesinurad on the Pharmacokinetics of Co-administered Drugs
Figure 2
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of lesinurad was eva luated in Sprague-Dawley rats and TgRasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received lesinurad for 91 to 100 weeks at oral doses up to 200 mg/kg/day (approximately 35 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in TgRasH2 mice that received lesinurad for 26 weeks at oral doses up to 125 and 250 mg/kg/day in male and female mice, respectively.
Lesinurad tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo rat bone marrow micronucleus assay.
Fertility and reproductive performance were unaff |
