Sodium zirconium cyclosilicate explained

Tradename:Lokelma
Dailymedid:Sodium zirconium cyclosilicate
Pregnancy Au:B1
Routes Of Administration:By mouth
Atc Prefix:V03
Atc Suffix:AE10
Legal Au:S4
Legal Au Comment:[1]
Legal Ca:Rx-only
Legal Ca Comment:[2]
Legal Us:Rx-only
Legal Us Comment:[3]
Legal Eu:Rx-only
Legal Status:Rx-only
Bioavailability:Not absorbed
Excretion:Feces
Cas Number:17141-74-1
Drugbank:DB14048
Unii:D652ZWF066
Kegg:D10727
Synonyms:ZS-9
Iupac Name:Silicic acid, sodium zirconium(4+) salt (3:2:1), hydrate
Chemical Formula:(2Na·H2O·3H4SiO4·H4ZrO6)n

Sodium zirconium cyclosilicate, sold under the brand name Lokelma, is a medication used to treat high blood potassium. Onset of effects occurs in one to six hours. It is taken by mouth.[4]

Common side effects include swelling and low blood potassium.[4] Use is likely safe in pregnancy and breastfeeding.[4] It works by binding potassium ions in the gastrointestinal tract which is then lost in the stool.[4] [5]

Sodium zirconium cyclosilicate was approved for medical use in the European Union and in the United States in 2018.[4] [6] [7] It was developed by AstraZeneca.[4]

Medical use

Sodium zirconium cyclosilicate is used to treat high blood potassium.[4] Onset of effects occurs in one to six hours.[4]

Mechanism of action

ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.[8] 11 zirconium silicates were screened by an iterative optimization process. ZS-9 selectively captures potassium ions, presumably by mimicking the actions of physiologic potassium channels.[9] ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract.

Background

See main article: Hyperkalemia.

Hyperkalemia is rare among those who are otherwise healthy.[10] Among those who are in hospital, rates are between 1% and 2.5%.[11] Common causes include kidney failure, hypoaldosteronism, and rhabdomyolysis.[12] A number of medications can also cause high blood potassium including spironolactone, NSAIDs, and angiotensin converting enzyme inhibitors.[12]

There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe.[13] However, if hyperkalemia causes any ECG change it is considered a medical emergency[13] due to a risk of potentially fatal abnormal heart rhythms and is treated urgently.[13] Potassium levels greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.[13] Several approaches are used to treat hyperkalemia.[13] Other approved potassium binders in the United States include patiromer and sodium polystyrene sulfonate.[14]

Hyperkalemia, particularly if severe, is a marker for an increased risk of death.[15] However, there is disagreement regarding whether a modestly elevated levels directly causes problems. One viewpoint is that mild to moderate hyperkalemia is a secondary effect that denotes underlying medical problems.[15] Accordingly, these problems are both proximate and ultimate causes of death,[15]

History

In the United States, regulatory approval of ZS-9 was rejected by the Food and Drug Administration (FDA) in May 2016, due to issues associated with manufacturing.[16] On 18 May 2018, the FDA approved sodium zirconium cyclosilicate for treatment of adults with hyperkalemia.[17]

It was first practically synthesized by UOP in the late 1990s. (reference -zirconium silicate and zirconium germate molecular sieves and the process of using the same, US Patent 5,888,472) the recognition of the unique ion exchange properties and the potential use to remove toxins from the body were identified shortly thereafter ("process for removing toxins from bodily fluids using zirconium or titanium microporous compositions, US Patent 6,332,985).

Research

One review found a decrease in potassium of 0.17 mEq/L at one hour and 0.67 mEq/L at 48 hours.[18]

It appears effective in people with chronic kidney disease, diabetes, and heart failure.[5] Use has been studied for up to a year.[5]

Further reading

Notes and References

  1. Web site: Lokelma APMDS . Therapeutic Goods Administration (TGA) . 24 May 2024 . 10 June 2024.
  2. Web site: Summary Basis of Decision (SBD) for Lokelma . . 23 October 2014 . 29 May 2022 . 31 May 2022 . https://web.archive.org/web/20220531045450/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00468&lang=en . live .
  3. Web site: Lokelma- sodium zirconium cyclosilicate powder, for suspension . DailyMed . 30 September 2022 . 27 February 2023 . 5 December 2022 . https://web.archive.org/web/20221205214856/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90bf8e28-748d-4e4b-a19f-9cf483370eff . live .
  4. Web site: Sodium Zirconium Cyclosilicate Monograph for Professionals . Drugs.com . 11 October 2019 . 1 August 2020 . https://web.archive.org/web/20200801164908/https://www.drugs.com/monograph/sodium-zirconium-cyclosilicate.html . live .
  5. Hoy SM . Sodium Zirconium Cyclosilicate: A Review in Hyperkalaemia . Drugs . 78 . 15 . 1605–1613 . October 2018 . 30306338 . 6433811 . 10.1007/s40265-018-0991-6 .
  6. Web site: Lokelma EPAR . European Medicines Agency (EMA) . 17 September 2018 . 11 October 2019 . 8 January 2021 . https://web.archive.org/web/20210108070818/https://www.ema.europa.eu/en/medicines/human/EPAR/lokelma . live .
  7. Web site: Drug Approval Package: Lokelma (sodium zirconium cyclosilicate) . U.S. Food and Drug Administration (FDA) . 8 June 2018 . 7 May 2020 . 13 April 2021 . https://web.archive.org/web/20210413050630/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207078Orig1s000TOC.cfm . live .
  8. Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307
  9. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS . Characterization of structure and function of ZS-9, a K+ selective ion trap . PLOS ONE . 9 . 12 . e114686 . 2014 . 25531770 . 4273971 . 10.1371/journal.pone.0114686 . 2014PLoSO...9k4686S . free .
  10. Kovesdy CP . Updates in hyperkalemia: Outcomes and therapeutic strategies . Reviews in Endocrine & Metabolic Disorders . 18 . 1 . 41–47 . March 2017 . 27600582 . 5339065 . 10.1007/s11154-016-9384-x .
  11. McDonald TJ, Oram RA, Vaidya B . 206907572 . Investigating hyperkalaemia in adults . BMJ . 351 . h4762 . October 2015 . 26487322 . 10.1136/bmj.h4762 .
  12. Lehnhardt A, Kemper MJ . Pathogenesis, diagnosis and management of hyperkalemia . Pediatric Nephrology . 26 . 3 . 377–84 . March 2011 . 21181208 . 3061004 . 10.1007/s00467-010-1699-3 .
  13. Book: Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu AS, Brenner BM . Brenner and Rector's The Kidney . Elsevier . 2012 . Chapter 17, page 672, 9th . 978-1-4160-6193-9.
  14. Watson M, Abbott KC, Yuan CM . Damned if you do, damned if you don't: potassium binding resins in hyperkalemia . Clinical Journal of the American Society of Nephrology . 5 . 10 . 1723–6 . October 2010 . 20798253 . 10.2215/CJN.03700410 . free .
  15. Elliott MJ, Ronksley PE, Clase CM, Ahmed SB, Hemmelgarn BR . Management of patients with acute hyperkalemia . CMAJ . 182 . 15 . 1631–5 . October 2010 . 20855477 . 2952010 . 10.1503/cmaj.100461 .
  16. News: FierceBiotech . AstraZeneca's $2.7B hyperkalemia drug ZS-9 rejected by FDA . Ben Adams . 27 May 2016 . 27 May 2016 . 28 May 2016 . https://web.archive.org/web/20160528134033/http://www.fiercebiotech.com/biotech/astrazeneca-s-2-7b-hyperkalemia-drug-zs-9-rejected-by-fda . live .
  17. Web site: Lokelma (Sodium zirconium cyclosilicate) FDA Approval History . 11 June 2018 . 12 June 2018 . https://web.archive.org/web/20180612144044/https://www.drugs.com/history/lokelma.html . live .
  18. Meaney CJ, Beccari MV, Yang Y, Zhao J . Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia . Pharmacotherapy . 37 . 4 . 401–411 . April 2017 . 28122118 . 5388568 . 10.1002/phar.1906 .