ients treated with Krystexxa 8 mg every 2 weeks had a creatinine clearance of ≤62.5 mL/min. No overall differences in efficacy were observed.
Overdosage
No reports of overdosage with Krystexxa have been reported. The maximum dose that has been administered as a single intravenous dose is 12 mg as uricase protein.
Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specific antidote has been identified.
Krystexxa Description
Krystexxa (pegloticase) is a uric acid specific enzyme which is a PEGylated product that consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated to monomethoxypoly(ethylene glycol) [mPEG] (10 kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricase subunit has a molecular weight of approximately 34 kDa per subunit. The average molecular weight of pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540 kDa.
Krystexxa is intended for intravenous infusion.
Krystexxa is a sterile, clear, colorless solution containing 8 mg/mL pegloticase in phosphate-buffered saline.
Krystexxa (pegloticase) concentrations are expressed as concentrations of uricase protein. Each mL of Krystexxa contains 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), 2.18 mg Disodium Hydrogen Phosphate Dihydrate (Na2HPO4•2H2O), 8.77 mg Sodium Chloride (NaCl), 0.43 mg Sodium Dihydrogen Phosphate Dihydrate (NaH2PO4•2H2O), and Water for Injection to deliver 8 mg of pegloticase (as uricase protein).
Krystexxa - Clinical Pharmacology
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.
Pharmacodynamics
Approximately 24 hours following the first dose of Krystexxa, mean plasma uric acid levels for subjects in the Krystexxa groups were 0.7 mg/dL for the Krystexxa 8 mg every 2 weeks group. In comparison, the mean plasma uric acid level for the placebo group was 8.2 mg/dL.
In a single-dose, dose-ranging trial, following 1-hour intravenous infusions of 0.5, 1, 2, 4, 8 or 12 mg of pegloticase in 24 patients with symptomatic gout (n=4 subjects/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 6 mg/dL for more than 300 hours was observed with doses of 8 mg and 12 mg.
Pharmacokinetics
Pegloticase levels were determined in serum based on measurements of uricase enzyme activity.
Following single intravenous infusions of 0.5 mg to 12 mg pegloticase in 23 patients 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.
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