Pegloticase

Pegloticase (trade name Krystexxa) is a medication for the treatment of severe, treatment-refractory, chronic gout. It is a third line treatment in those in whom other treatments are not tolerated.[1] The drug is administered by infusion intravenously.

Pegloticase
Clinical data
Trade namesKrystexxa, Puricase
AHFS/Drugs.comMonograph
MedlinePlusa611015
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityN/A
Elimination half-life10–12 days
Identifiers
CAS Number
IUPHAR/BPS
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC1549H2430N408O448S8 (peptide monomer)
Molar mass497 kg/mol (polymer-modified tetramer) g·mol−1
 NY (what is this?)  (verify)

It was developed by Savient Pharmaceuticals.[2][3] It was approved in the United States in 2010, after two clinical trials found it lowered uric acid levels and reduced deposits of uric acid crystals in joints and soft tissue. The European Medicines Agency (EMA) granted marketing authorization in 2013 for treatment of disabling tophaceous gout. In 2016 this authorization was ended in Europe.[4]

Medical uses

It is an option for the 3% of people with gout who are intolerant to other medications.[5] Pegloticase is given as an intravenous infusion every two weeks,[5] and has been found to reduce uric acid levels in this population.[6] It is likely useful for tophi but has a high rate of side effects.[7] About 40% of people develop resistance to the medication over time.[1]

Side effects

In individuals with glucose-6-phosphate dehydrogenase deficiency, pegloticase may precipitate a severe, life-threatening hemolysis with methemoglobinemia; it is therefore contraindicated in such individuals. Pegloticase may also show immunogenicity.[8]

Mechanism of action

Pegloticase is a recombinant porcine-like uricase. Similarly to rasburicase, it metabolises uric acid to allantoin. This reduces the risk of precipitates, since allantoin is five to ten times more soluble than uric acid.

In contrast to rasburicase, pegloticase is pegylated to increase its elimination half-life from about eight hours to ten or twelve days, and to decrease the immunogenicity of the foreign uricase protein. This modification allows for an application just once every two to four weeks, making this drug suitable for long-term treatment.[9]

Chemistry

Pegloticase is a tetrameric protein composed of four identical chains of about 300 amino acids each. Approximately nine of the 30 lysine residues in each chain are pegylated. These PEG chains consist of about 225 ethylene glycol units each (10 kg/mol PEG).[2]

References
  1. Dalbeth, N; Merriman, TR; Stamp, LK (22 October 2016). "Gout". Lancet. 388 (10055): 2039–2052. doi:10.1016/s0140-6736(16)00346-9. PMID 27112094. S2CID 208790780.
  2. Statement on a nonproprietary name adopted by the USAN Council
  3. "Savient Pharmaceuticals: Uricase". Archived from the original on 2006-07-10. Retrieved 2009-03-29.
  4. "Krystexxa Withdrawal of the marketing authorisation in the European Union" (PDF). Retrieved 25 March 2017.
  5. "FDA approves new drug for gout". FDA. September 14, 2010.
  6. Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, Vázquez-Mellado J, White WB, Lipsky PE, Horowitz Z, Huang W, Maroli AN, Waltrip RW, Hamburger SA, Becker MA (Aug 17, 2011). "Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials". JAMA: The Journal of the American Medical Association. 306 (7): 711–20. doi:10.1001/jama.2011.1169. PMID 21846852.
  7. Sriranganathan, MK; Vinik, O; Bombardier, C; Edwards, CJ (Oct 20, 2014). "Interventions for tophi in gout". The Cochrane Database of Systematic Reviews. 10 (10): CD010069. doi:10.1002/14651858.CD010069.pub2. PMID 25330136.
  8. Abraham J. Domb, Neeraj Kumar (2 August 2011). Biodegradable Polymers in Clinical Use and Clinical Development. John Wiley & Sons. ISBN 9781118015803.
  9. Biggers, K; Scheinfeldt, N (2008). "Pegloticase, a polyethylene glycol conjugate of uricase for the potential intravenous treatment of gout". Current Opinion in Investigational Drugs. 9 (4): 422–429. PMID 18393109.
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