ZS-9

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ZS-9 (sodium zirconium cyclosilicate) is a selective oral sorbent that traps potassium ions throughout the gastrointestinal tract. It is being developed by ZS Pharma for the treatment of hyperkalemia (elevated serum potassium levels).[1]

Background[edit]

Main article: Hyperkalemia

Hyperkalemia occurs in 3 to 10% of hospitalized patients[2] but is often mild. Hyperkalemia can arise from impaired renal function, potassium-sparing diuretics and renin-angiotensin system blockers (e.g., ACE inhibitors, angiotensin receptor blockers, spironolactone) and diabetes mellitus.[2][3][4][5]

There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe.[6] However, if hyperkalemia causes any ECG change it is considered a medical emergency[6] due to a risk of potentially fatal abnormal heart rhythms (arrhythmia) and is treated urgently.[6] serum potassium concentrations greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.[6]

Hyperkalemia, particularly if severe, is a marker for an increased risk of death.[2] However, there is disagreement regarding whether a modestly elevated serum potassium level directly causes significant problems. One viewpoint is that mild to moderate hyperkalemia is an secondary effect that denotes significant underlying medical problems.[2] Accordingly, these problems are both proximate and ultimate causes of death,[2] and adjustment of potassium may not be helpful. Alternatively, hyperkalemia may itself be an independent risk factor for cardiovascular mortality.[7]

Several approaches are used in treatment of hyperkalemia,[6] but currently the only product approved by the U.S. Food and Drug Administration (FDA) to treat hyperkalemia is sodium polystyrene sulfonate (Kayexalate),[8] an organic ion-exchange resin that nonspecifically binds cations (e.g., calcium, potassium, magnesium) in the gastrointestinal tract. The effectiveness of sodium polystyrene sulfonate has been questioned: a study in healthy subjects showed that laxatives alone were almost as effective in increasing potassium secretion as laxatives plus Kayexalate.[9] In addition, use of sodium polystyrene sulfonate, particularly if formulated with high sorbitol content, is uncommonly but convincingly associated with colonic necrosis.[6][8][10][11]

Mechanism of action[edit]

ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.[12] 12 zirconium silicates were screened by an iterative optimization process.[citation needed] ZS-9 selectively captures potassium ions by mimicking the actions of physiologic potassium channels.[citation needed] 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.

Clinical studies[edit]

A phase 2 clinical trial in 90 patients with chronic kidney disease and mild-to-moderate hyperkalemia found a significantly greater reduction in serum potassium with ZS-9 than placebo. ZS-9 was well tolerated, with a single adverse event (mild constipation).[13]

A double-blind, phase 3 clinical trial in 753 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin-angiotensin system blockers compared ZS-9 with placebo.[14] Patients were randomly assigned to receive either ZS-9 (1.25g, 2.5g, 5g, or 10g) or placebo 3 times daily for 48 hours (acute phase). Patients who achieved normokalemia (serum potassium of 3.5-4.9mmol/L) were randomly assigned to receive ZS-9 or placebo once daily for 12 additional days (maintenance phase). At the end of the acute phase, serum potassium significantly decreased in the 2.5g, 5g, and 10g ZS-9 groups. During the maintenance phase, once daily 5g or 10g ZS-9 maintained serum potassium at normal levels. Adverse events, including specifically gastrointestinal effects, were similar with either ZS-9 or placebo.[14]

A double-blind, phase 3 clinical trial in 258 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin-angiotensin system blockers compared ZS-9 with placebo.[15] All patients received 10g ZS-9 three times daily for 48 hours in the initial open-label phase. Patients who achieved normokalemia (serum potassium 3.5-5.0mEq/L) were randomly assigned to receive either ZS-9 (5g, 10g, or 15g) or placebo once daily for 28 days (double-blind phase). 98% of patients (n=237) achieved normokalemia during the open-label phase. During the double-blind phase, once daily 5g, 10g, and 15g ZS-9 maintained serum potassium at normal levels in a significantly higher proportion of patients (80%, 90%, and 94%, respectively) than placebo (46%). Adverse events were generally similar with either ZS-9 or placebo. Hypokalemia occurred in more patients in the 10g and 15g ZS-9 groups (10% and 11%, respectively), versus none in the 5g ZS-9 or placebo groups.[15]

References[edit]

  1. ^ ZS-9. ZS-Pharma. [1]
  2. ^ a b c d e 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.  edit
  3. ^ Stevens, M. S.; Dunlay, R. W. (2000). International Urology and Nephrology 32 (2): 177. doi:10.1023/A:1007135517950.  Missing or empty |title= (help) edit
  4. ^ Navaneethan, S. D.; Yehnert, H.; Moustarah, F.; Schreiber, M. J.; Schauer, P. R.; Beddhu, S. (2009). "Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis". Clinical Journal of the American Society of Nephrology 4 (10): 1565. doi:10.2215/CJN.02250409.  edit
  5. ^ Tamirisa, K. P.; Aaronson, K. D.; Koelling, T. M. (2004). "Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure". American Heart Journal 148 (6): 971. doi:10.1016/j.ahj.2004.10.005.  edit
  6. ^ a b c d e f 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. 
  7. ^ Fang, J.; Madhavan, S.; Cohen, H.; Alderman, M. H. (2000). "Serum potassium and cardiovascular mortality". Journal of General Internal Medicine 15 (12): 885. doi:10.1046/j.1525-1497.2000.91021.x.  edit
  8. ^ a b 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.  edit
  9. ^ Emmett, M.; Hootkins, R. E.; Fine, K. D.; Santa Ana, C. A.; Porter, J. L.; Fordtran, J. S. (1995). "Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion". Gastroenterology 108 (3): 752. doi:10.1016/0016-5085(95)90448-4.  edit
  10. ^ Sterns, R. H.; Rojas, M.; Bernstein, P.; Chennupati, S. (2010). "Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective?". Journal of the American Society of Nephrology 21 (5): 733–5. doi:10.1681/ASN.2010010079. PMID 20167700.  edit
  11. ^ Kamel, K. S.; Schreiber, M. (2012). "Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia?". Nephrology Dialysis Transplantation 27 (12): 4294–7. doi:10.1093/ndt/gfs293. PMID 22989741.  edit
  12. ^ Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307
  13. ^ Ash SR, et al. "Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients." American Society of Nephrology 2013 conference, Late-Breaking Abstract.
  14. ^ a b Packham DK, et al (2014). "Sodium zirconium cyclosilicate in hyperkalemia". New England Journal of Medicine. doi:10.1056/NEJMoa1411487. 
  15. ^ a b Kosiborod M, et al (2014). "Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia". Journal of the American Medical Association. doi:10.1001/jama.2014.15688.