Rasburicase

Rasburicase
Names
Trade namesElitek, Fasturtec
IUPAC name
  • Aspergillus urate oxidase
Clinical data
Main usesHigh uric acid due to tumor lysis syndrome[1]
Side effectsNausea, fever, swelling, anxiety, headache, diarrhea, low phosphate[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B2
  • US: C (Risk not ruled out)
    Routes of
    use    		Intravenous infusion
    Typical dose200 ucg/kg[2]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    BioavailabilityN/A
    Elimination half-life18 hrs
    Chemical and physical data
    FormulaC1521H2381N417O461S7
    Molar mass34109.66 g·mol−1

    Rasburicase, sold under the brand names Elitek among others, is a medication used for high uric acid levels that occur as a result of tumor lysis syndrome.[1] It is given by gradual injection into a vein.[1]

    Common side effects include nausea, fever, swelling, anxiety, headache, diarrhea, and low phosphate.[1] Other side effects may include anaphylaxis and methemoglobinemia.[3] It should not be used in people with G6PD deficiency.[3] It is the urate oxidase enzyme created by recombinant DNA technology.[3]

    Rasburicase was approved for medical use in Europe in 2001 and the United States in 2002.[1][4] It is on the World Health Organization's List of Essential Medicines.[5] In the United Kingdom it costs the NHS about £350 per 7.5mg vial as of 2021.[2] This amount in the United States costs about 5,000 USD.[6]

    Medical uses

    Rasburicase is approved for use by the U.S. Food and Drug Administration (and European counterparts) for the prevention and treatment of tumor lysis syndrome (TLS)[7] in people receiving chemotherapy for hematologic cancers such as leukemias and lymphomas. However, it is not clear if it results in important benefits such as decreased kidney problems or decreased risk of death as of 2017.[8]

    It is being investigated for treating severely high blood levels of uric acid from other sources. For example, it has been used for hyperuricemia in gout,[9] in other rheumatologic conditions, and in rhabdomyolysis with kidney failure.[10]

    Dosage

    It is generally used at a dose of 200 micrograms/kg per day.[2] It may be given for up to a week.[2]

    Side effects

    Rasburicase administration can cause anaphylaxis (incidence unknown); methemoglobinemia may occur in susceptible individuals such as those with G6PDH deficiency due to the production of hydrogen peroxide in the urate oxidase reaction.[11] Testing patients for G6PDH deficiency prior to starting a course of rasburicase has been recommended.[11]

    Pharmacology

    Mechanism of Action

    In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite allantoin with carbon dioxide and hydrogen peroxide as byproducts in the chemical reaction.[11]

    Pharmacodynamics

    The measurement of plasma uric acid was used to evaluate the effectiveness of rasburicase in clinical studies. Following administration of either 0.15 or 0.20 mg/kg rasburicase daily for up to 5 days, plasma uric acid levels decreased within 4 hours and were maintained below 7.5 mg/dL in 98% of adult and 90% of pediatric patients for at least 7 days. There was no evidence of a dose response effect on uric acid control for doses between 0.15 and 0.20 mg/kg rasburicase.[12]

    Pharmacokinetics

    The pharmacokinetics of rasburicase were evaluated in both pediatric and adult patients with leukemia, lymphoma or other hematological malignancies. Rasburicase exposure, as measured by AUC0-24 hr and Cmax, tended to increase with a dose range from 0.15 to 0.2 mg/kg. The mean terminal half-life was similar between pediatric and adult patients and ranged from 15.7 to 22.5 hours. The mean volume of distribution of rasburicase ranged from 110 to 127 mL/kg in pediatric patients and from 75.8 to 138 mL/kg in adult patients, respectively. Minimal accumulation of rasburicase ( < 1.3 fold) was observed between days 1 and 5 of dosing. In adults, age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=22).[12]

    Chemistry

    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.[11] 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.[11] Rasburicase is a tetrameric protein with identical subunits. Each subunit is made up of a single 301 amino acid polypeptide chain with a molecular mass of about 34 kDa. The drug product is a sterile, white to off-white, lyophilized powder intended for intravenous administration following reconstitution with a diluent. Elitek (rasburicase) is supplied in 3 mL and 10 mL colorless, glass vials containing rasburicase at a concentration of 1.5 mg/mL after reconstitution.[12]

    Society and culture

    Economics

    Rasburicase is much more expensive than conventional therapy.[13]

    References

    1. 1 2 3 4 5 6 "DailyMed - ELITEK- rasburicase kit". dailymed.nlm.nih.gov. Archived from the original on 20 March 2021. Retrieved 16 October 2021.
    2. 1 2 3 4 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 994. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    3. 1 2 3 "Rasburicase Monograph for Professionals". Drugs.com. Archived from the original on 5 August 2019. Retrieved 16 October 2021.
    4. ↑ "Fasturtec". Archived from the original on 28 December 2020. Retrieved 16 October 2021.
    5. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
    6. ↑ "Elitek Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 20 January 2021. Retrieved 16 October 2021.
    7. ↑ Ho VQ, Wetzstein GA, Patterson SG, Bradbury R (April 2006). "Abbreviated rasburicase dosing for the prevention and treatment of hyperuricemia in adults at risk for tumor lysis syndrome". Supportive Cancer Therapy. 3 (3): 178–82. doi:10.3816/SCT.2006.n.016. PMID 18632493.
    8. ↑ Cheuk, Daniel Kl; Chiang, Alan Ks; Chan, Godfrey Cf; Ha, Shau Yin (8 March 2017). "Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer". The Cochrane Database of Systematic Reviews. 3: CD006945. doi:10.1002/14651858.CD006945.pub4. ISSN 1469-493X. PMC 6464610. PMID 28272834.
    9. ↑ Cammalleri L, Malaguarnera M (2007). "Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout". International Journal of Medical Sciences. 4 (2): 83–93. doi:10.7150/ijms.4.83. PMC 1838823. PMID 17396159.
    10. ↑ Lin, PY; et al. (2011), "Rasburicase improves hyperuricemia in patients with acute kidney injury secondary to rhabdomyolysis caused by ecstasy intoxication and exertional heat stroke", Pediatr Crit Care Med, 12 (6): e424–e427, doi:10.1097/PCC.0b013e3182192c8d, PMID 21572370, S2CID 23910863.
    11. 1 2 3 4 5 Wilson FP, Berns JS (October 2012). "Onco-nephrology: tumor lysis syndrome". Clin J Am Soc Nephrol. 7 (10): 1730–9. doi:10.2215/CJN.03150312. PMID 22879434. Archived from the original on 2019-08-05. Retrieved 2021-03-11.
    12. 1 2 3 "Elitek (rasburicase)". Rxlist. Archived from the original on 2016-03-04. Retrieved 2021-03-11.
    13. ↑ Reinders MK, van Roon EN, Brouwers JR, Jansen TL (March 2005). "A costly therapeutic dilemma in tophaceous gout: is etanercept or rasburicase preferable?". Annals of the Rheumatic Diseases. 64 (3): 516, author reply 516. doi:10.1136/ard.2003.017087corr1. PMC 1755382. PMID 15708917.
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