Pegloticase

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Pegloticase
Clinical data
Trade names Krystexxa, Puricase
AHFS/Drugs.com Monograph
MedlinePlus a611015
License data
Routes of
administration 		Intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability N/A
Elimination half-life 10–12 days
Identifiers
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C1549H2430N408O448S8
Molar mass 34193.37 g·mol−1
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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 effective or are not tolerated. [2] The drug is administered by infusion intravenously. Since October 2023, Amgen Inc. has been the marketer of pegloticase in the U.S.

Contents

It was developed by Savient Pharmaceuticals. [3] [4] 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 at the request of Horizon Therapeutics PLC in Europe. [5]

Medical uses

It is an option for the 3% of people with gout who are intolerant of or nonresponsive to other medications. [6] Pegloticase is given as an intravenous infusion every two weeks, [6] and has been found to reduce uric acid levels in this population. [7] There is moderate quality evidence that It is useful for tophi but has a high rate of side effects and withdrawals due to adverse events. [8] About 40% of people develop resistance to the medication over time. [2] Co-administration of methotrexate increases the response rate approximately two-fold.

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, which can be diminished by co-administration with methotrexate. [9]

Mechanism of action

Pegloticase is a PEGylated recombinant porcine-like uricase. Similarly to rasburicase, it metabolises uric acid to allantoin. This reduces the risk of urate 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 to twelve days, and to decrease the immunogenicity of the foreign uricase protein. This modification allows for a dosing interval of two to four weeks, increasing its suitability for long-term treatment. [10]

Chemistry

Pegloticase is a tetrameric protein composed of four identical chains of about 300 amino acids each. Approximately ten 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). [3]

Related Research Articles

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

<span class="mw-page-title-main">Gout</span> Form of arthritis causing swollen joints

Gout is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.

<span class="mw-page-title-main">Polyethylene glycol</span> Chemical compound

Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular weight. The structure of PEG is commonly expressed as H−(O−CH2−CH2)n−OH.

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Hyperuricemia</span> Excess uric acid in the blood

Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 mg/dL for males, and 5.5 mg/dL for youth are defined as hyperuricemia. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body, and the amount of urate that is excreted in urine or through the gastrointestinal tract. Hyperuricemia may be the result of increased production of uric acid, decreased excretion of uric acid, or both increased production and reduced excretion.

Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off (lysed) from the treatment, releasing their contents into the bloodstream. This occurs most commonly after the treatment of lymphomas and leukemias and in particular when treating non-Hodgkin lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia. This is a potentially fatal complication and patients at increased risk for TLS should be closely monitored while receiving chemotherapy and should receive preventive measures and treatments as necessary. TLS can also occur on its own although this is less common.

<span class="mw-page-title-main">Urate oxidase</span> Pseudogene in the species Homo sapiens

The enzyme urate oxidase (UO), uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the oxidation of uric acid to 5-hydroxyisourate:

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase, sold under the brand name Elitek in the US and Fasturtec in the EU, is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

<span class="mw-page-title-main">Asparaginase</span> Enzyme used as medication and in food manufacturing

Asparaginase is an enzyme that is used as a medication and in food manufacturing. As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). It is given by injection into a vein, or muscle. A pegylated version is also available. In food manufacturing it is used to decrease acrylamide.

<span class="mw-page-title-main">Probenecid</span> Chemical compound

Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis. It is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and is an immunosuppressive drug. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds. It is administered by intravenous infusion. The fixed-dose combination ocrelizumab/hyaluronidase is administered by subcutaneous injection.

<span class="mw-page-title-main">Inotuzumab ozogamicin</span> Chemical compound

Inotuzumab ozogamicin, sold under the brand name Besponsa, is an antibody-drug conjugate medication used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia. It is administered by intravenous infusion.

<span class="mw-page-title-main">PEGylation</span> Chemical reaction

PEGylation is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as PEGylated. PEGylation affects the resulting derivatives or aggregates interactions, which typically slows down their coalescence and degradation as well as elimination in vivo.

<span class="mw-page-title-main">Macrogol</span> Medication for constipation, classified as an osmotic laxative

Macrogol, also called polyethylene glycol (PEG), is used as a laxative to treat constipation in children and adults. It is taken by mouth. Benefits usually occur within three days. Generally it is only recommended for up to two weeks. It is also used as an excipient. It is also used to clear the bowels before a colonoscopy, when the onset of the laxative effect is more rapid, typically within an hour.

Ethylene glycol poisoning is poisoning caused by drinking ethylene glycol. Early symptoms include intoxication, vomiting and abdominal pain. Later symptoms may include a decreased level of consciousness, headache, and seizures. Long term outcomes may include kidney failure and brain damage. Toxicity and death may occur after drinking even in a small amount as ethylene glycol is more toxic than other diols.

<span class="mw-page-title-main">Naloxegol</span> Medication used in the treatment for Opioid-Induced Constipation

Naloxegol is a peripherally acting μ-opioid receptor antagonist developed by AstraZeneca, licensed from Nektar Therapeutics, for the treatment of opioid-induced constipation. It was approved in 2014 in adult patients with chronic, non-cancer pain. Doses of 25 mg were found safe and well tolerated for 52 weeks. When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">Mirvetuximab soravtansine</span> Pharmaceutical drug

Mirvetuximab soravtansine, sold under the brand name Elahere, is a medication used as a treatment for epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Mirvetuximab soravtansine is a folate receptor alpha directed antibody and microtubule inhibitor conjugate.

Emapalumab, sold under the brand name Gamifant, is an anti-interferon-gamma (IFNγ) antibody medication used for the treatment of hemophagocytic lymphohistiocytosis (HLH), which has no cure.

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References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. 1 2 Dalbeth N, Merriman TR, Stamp LK (October 2016). "Gout". Lancet. 388 (10055): 2039–2052. doi:10.1016/s0140-6736(16)00346-9. PMID   27112094. S2CID   208790780.
  3. 1 2 "Pegloticase" (PDF). Statement on a nonproprietary name adopted by the USAN Council. Archived from the original (PDF) on 4 June 2011.
  4. ↑ "Savient Pharmaceuticals: Uricase". Archived from the original on 2006-07-10. Retrieved 2009-03-29.
  5. ↑ "Krystexxa Withdrawal of the marketing authorisation in the European Union" (PDF). Archived from the original (PDF) on 26 March 2017. Retrieved 25 March 2017.
  6. 1 2 "FDA approves new drug for gout". FDA. September 14, 2010.
  7. ↑ Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, et al. (August 2011). "Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials". JAMA. 306 (7): 711–720. doi: 10.1001/jama.2011.1169 . hdl: 10342/7960 . PMID   21846852.
  8. ↑ Sriranganathan MK, Vinik O, Pardo Pardo J, Bombardier C, Edwards CJ (August 2021). "Interventions for tophi in gout". The Cochrane Database of Systematic Reviews. 8 (8): CD010069. doi:10.1002/14651858.CD010069.pub3. PMC   8406833 . PMID   34379791.
  9. ↑ Abraham J. Domb, Neeraj Kumar (2 August 2011). Biodegradable Polymers in Clinical Use and Clinical Development. John Wiley & Sons. ISBN   9781118015803.
  10. ↑ Biggers K, Scheinfeld N (April 2008). "Pegloticase, a poly(ethylene 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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