Sodium zirconium cyclosilicate

Sodium zirconium cyclosilicate (ZS-9), sold under the brand name Lokelma, is a medication used to treat high blood potassium.[1] Onset of effects occurs in one to six hours.[1] It is taken by mouth.[1]

Sodium zirconium cyclosilicate
Crystal structure of ZS-9. Blue spheres  =  oxygen atoms, red spheres  =  zirconium atoms, green spheres  =  silicon atoms.
Clinical data
Trade namesLokelma
AHFS/Drugs.comMonograph
Routes of
administration		By mouth
ATC code
  • none
Legal status
Legal status
  • US: Rx-only
Pharmacokinetic data
BioavailabilityNot absorbed
ExcretionStool
Identifiers
CAS Number
UNII
KEGG
Chemical and physical data
Formula(2Na·H2O·3H4SiO4·H4ZrO6)n

Common side effects include swelling and low blood potassium.[1] Use is likely safe in pregnancy and breastfeeding.[1] It works by binding potassium ions in the gastrointestinal tract which is than lost in the stool.[1][2]

Sodium zirconium cyclosilicate was approved for medical use in the Europe and the United States in 2018.[1][3] It was developed by AstraZeneca.[1] In the United States it costs about $US24 per dose.[4] In the United Kingdom as of 2019 it costs the NHS about £7.12 per dose.[5]

Medical use

Sodium zirconium cyclosilicate is used to treat high blood potassium.[1] Onset of effects occurs in one to six hours.[1]

One review found a decrease in potassium of 0.17 mEq/L at one hour and 0.67 mEq/L at 48 hours.[6]

It appears effective in people with chronic kidney disease, diabetes, and heart failure.[2] Use has been studied for up to a year.[2]

Mechanism of action
Cross-sections of ZS-9 pores with three different ions (K⁺ = potassium, Na⁺ = sodium, Ca²⁺ = calcium). The specificity for potassium is thought to be caused by the diameter and composition of the pores, which resembles potassium channels.

ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.[7] 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.[8] 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. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized.

Background
Main article: Hyperkalemia

Hyperkalemia is rare among those who are otherwise healthy.[9] Among those who are in hospital, rates are between 1% and 2.5%.[10] Common causes include kidney failure, hypoaldosteronism, and rhabdomyolysis.[11] A number of medications can also cause high blood potassium including spironolactone, NSAIDs, and angiotensin converting enzyme inhibitors.[11]

There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe.[12] However, if hyperkalemia causes any ECG change it is considered a medical emergency[12] due to a risk of potentially fatal abnormal heart rhythms and is treated urgently.[12] Potassium levels greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.[12] Several approaches are used to treat hyperkalemia.[12] Other approved potassium binders in the United States include patiromer and sodium polystyrene sulfonate.[13]

Hyperkalemia, particularly if severe, is a marker for an increased risk of death.[14] 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.[14] Accordingly, these problems are both proximate and ultimate causes of death,[14]

History

Regulatory

In the United States, regulatory approval of ZS-9 was rejected by the Food and Drug Administration in May 2016 due to issues associated with manufacturing.[15] On May 18, 2018, the FDA approved sodium zirconium cyclosilicate for treatment of adults with hyperkalemia.[16]

References
  1. "Sodium Zirconium Cyclosilicate Monograph for Professionals". Drugs.com. Retrieved 11 October 2019.
  2. Hoy, SM (October 2018). "Sodium Zirconium Cyclosilicate: A Review in Hyperkalaemia". Drugs. 78 (15): 1605–1613. doi:10.1007/s40265-018-0991-6. PMC 6433811. PMID 30306338.
  3. "Lokelma". European Medicines Agency. 17 September 2018. Retrieved 11 October 2019.
  4. "Lokelma Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 11 October 2019.
  5. "SODIUM ZIRCONIUM CYCLOSILICATE | Medicinal forms | BNF content published by NICE". webcache.googleusercontent.com. NICE. Retrieved 11 October 2019.
  6. Meaney, CJ; Beccari, MV; Yang, Y; Zhao, J (April 2017). "Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia". Pharmacotherapy. 37 (4): 401–411. doi:10.1002/phar.1906. PMC 5388568. PMID 28122118.
  7. Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307
  8. =Stavros, F (2014). "Characterization of Structure and Function of ZS-9, a K⁺ Selective Ion Trap". PLOS ONE. 9 (12): e114686. Bibcode:2014PLoSO...9k4686S. doi:10.1371/journal.pone.0114686. PMC 4273971. PMID 25531770.
  9. Kovesdy, CP (6 September 2016). "Updates in hyperkalemia: Outcomes and therapeutic strategies". Reviews in Endocrine & Metabolic Disorders. 18 (1): 41–47. doi:10.1007/s11154-016-9384-x. PMC 5339065. PMID 27600582.
  10. McDonald, TJ; Oram, RA; Vaidya, B (20 October 2015). "Investigating hyperkalaemia in adults". BMJ (Clinical Research Ed.). 351: h4762. doi:10.1136/bmj.h4762. PMID 26487322.
  11. Lehnhardt, A; Kemper, MJ (March 2011). "Pathogenesis, diagnosis and management of hyperkalemia". Pediatric Nephrology (Berlin, Germany). 26 (3): 377–84. doi:10.1007/s00467-010-1699-3. PMC 3061004. PMID 21181208.
  12. Taal, M.W.; Chertow, G.M.; Marsden, P.A.; Skorecki, K.; Yu, A.S.L.; Brenner, B.M. (2012). Brenner and Rector's The Kidney (Chapter 17, page 672, 9th ed.). Elsevier. ISBN 978-1-4160-6193-9.
  13. Watson, M.; Abbott, K. C.; Yuan, C. M. (2010). "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. doi:10.2215/CJN.03700410. PMID 20798253.
  14. Elliott, M. J.; Ronksley, P. E.; Clase, C. M.; Ahmed, S. B.; Hemmelgarn, B. R. (2010). "Management of patients with acute hyperkalemia". Canadian Medical Association Journal. 182 (15): 1631–5. doi:10.1503/cmaj.100461. PMC 2952010. PMID 20855477.
  15. Ben Adams (May 27, 2016). "AstraZeneca's $2.7B hyperkalemia drug ZS-9 rejected by FDA". FierceBiotech.
  16. "Lokelma (Sodium zirconium cyclosilicate) FDA Approval History".

Further reading
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