;2H2O), and Water for Injection to deliver 8mg of pegloticase (as uricase protein).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
KRYSTEXXA is a uric acid specific enzyme which is a recombinant uricase and achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water soluble purine metabolite. It is readily eliminated, primarily by renal excretion.
12.2 Pharmacodynamics
Approximately 24hours following the first dose of KRYSTEXXA, mean plasma uric acid levels for subjects in the KRYSTEXXA groups were 0.7mg/dL for the KRYSTEXXA 8mg every 2weeks group. In comparison, the mean plasma uric acid level for the placebo group was 8.2mg/dL.
In a single-dose, dose-ranging trial, following 1-hour intravenous infusions of 0.5, 1, 2, 4, 8 or 12mg of pegloticase in 24patients with symptomatic gout (n=4subjects/dose group), plasma uric acid decreased with increasing pegloticase dose or concentrations. The duration of suppression of plasma uric acid appeared to be positively associated with pegloticase dose. Sustained decrease in plasma uric acid below the solubility concentration of 6mg/dL for more than 300hours was observed with doses of 8mg and 12mg.
12.3 Pharmacokinetics
Pegloticase levels were determined in serum based on measurements of uricase enzyme activity.
Following single intravenous infusions of 0.5mg to 12mg pegloticase in 23patients with symptomatic gout, maximum serum concentrations of pegloticase increased in proportion to the dose administered.
The population pharmacokinetic analysis showed that age, sex, weight, and creatinine clearance did not influence the pharmacokinetics of pegloticase. Significant covariates included in the model for determining clearance and volume of distribution were found to be body surface area and anti-pegloticase antibodies.
The pharmacokinetics of pegloticase has not been studied in children and adolescents.
No formal studies were conducted to examine the effects of either renal or hepatic impairment on pegloticase pharmacokinetics.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to eva luate the carcinogenic potential of pegloticase.
The genotoxic potential of pegloticase has not been eva luated.
Fertility studies in animals have not been performed.
13.2 Animal Toxicology and/or Pharmacology
In a 12-week intravenous repeat-dose study in dogs, there was a dose-dependent increase in vacuolated macrophages in the spleen. The presence of vacuolated macrophages likely reflects accumulated removal of injected pegloticase (foreign) material from the circulation. There was no evidence of degeneration, inflammation, or necrosis associated with the vacuoles findings, however there was evidence of decreased functional response to liposaccharides.
In a 39-week, repeat dose dog study, there was a dose dependent increase in vacuolated cells in several organs, including the spleen, adrenal gland, liver, heart, duodenum and jejunum. In the spleen, liver, duodenum and jejunum, these vacuoles were within macrophages and most likely represented phagocytic removal of pegloticase from the circulation. However, the vacuolated cells in the heart and adrenal gland did not stain as macrophages. In the aortic outflow tract of the heart, vacuoles were in the cytoplasm of endothelial ce |
